Annual Review of Nutrition

Vitamin A and Retinoic

Acid in Cognition and
Cognitive Disease
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Marta U. Wołoszynowska-Fraser,1
Azita Kouchmeshky,2 and Peter McCaffery2
1
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224, USA
2
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD,
Scotland, United Kingdom; email: [email protected]

Annu. Rev. Nutr. 2020. 40:247–72 Keywords

The Annual Review of Nutrition is online at
neuroplasticity, Alzheimer’s disease, schizophrenia, autism, aging,
nutr.annualreviews.org
hippocampus
https://doi.org/10.1146/annurev-nutr-122319-
034227 Abstract
Copyright © 2020 by Annual Reviews.
The history of vitamin A goes back over one hundred years, but our real-
All rights reserved
ization of its importance for the brain and cognition is much more recent.
The brain is more efficient than other target tissues at converting vitamin A
to retinoic acid (RA), which activates retinoic acid receptors (RARs). RARs
regulate transcription, but their function in the cytoplasm to control nonge-
nomic actions is also crucial. Controlled synthesis of RA is essential for reg-
ulating synaptic plasticity in regions of the brain involved in learning and
memory, such as the hippocampus. Vitamin A deficiency results in a deteri-
oration of these functions, and failure of RA signaling is perhaps associated
with normal cognitive decline with age as well as with Alzheimer’s disease.
Further, several psychiatric and developmental disorders that disrupt cog-
nition are also linked with vitamin A and point to their possible treatment
with vitamin A or RA.

247
 Contents
1. VITAMIN A METABOLISM AND MOLECULAR ACTION
IN THE BRAIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
1.1. Vitamin A Transport to the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
1.2. Vitamin A Function in the Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
2. THE NEED FOR VITAMIN A AND RETINOIC ACID IN THE
HIPPOCAMPUS TO CONTROL NEUROPLASTICITY ESSENTIAL
FOR LEARNING AND MEMORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
2.1. Control of Retinoic Acid Synthesis in the Hippocampus . . . . . . . . . . . . . . . . . . . . . 249
2.2. Retinoic Acid and Neuroplasticity in the Hippocampus: Long-Term
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Potentiation, Long-Term Depression, and Neurogenesis . . . . . . . . . . . . . . . . . . . . 251

2.3. Retinoic Acid and Neuroplasticity in the Hippocampus: Homeostatic
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Synaptic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

2.4. Retinoic Acid Regulates Cognition by Controlling the Neurotransmitter
Acetylcholine and Mammalian Target of Rapamycin . . . . . . . . . . . . . . . . . . . . . . . . 254
3. INVOLVEMENT OF VITAMIN A AND RETINOIC ACID
IN COGNITIVE DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
3.1. Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
3.2. Schizophrenia and Schizoaffective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
3.3. Age-Related Dementia and Cognitive Deficit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
3.4. Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
4. VITAMIN A AS A COGNITIVE ENHANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
5. CONCLUSION AND THE FUTURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

1. VITAMIN A METABOLISM AND MOLECULAR ACTION

IN THE BRAIN
The brain was not an organ that stood out in the early history of vitamin A research and this
remained true up to the 1990s (98). Early studies of deficiency indicated the dependence of the
eye, skin, immune and reproductive systems, and developing embryo on vitamin A; however, the
effects of vitamin A deficiency (VAD) on the adult brain, with the exception of the medulla, were
not apparent (64). Nor is vitamin A in the form of retinol or retinyl esters prominent in the brain,
in contrast to tissues such as the eye, which uses vitamin A in its visual pigment. Levels of vitamin A
in the brain are similar to those in many other tissues with just moderate vitamin A demands. This
knowledge directed vitamin A research away from brain function in the past. However, although
the brain is not comparable to the eye in terms of vitamin A content, there is “more than meets
the eye” when it comes to function and the brain may be able to utilize lower amounts of vitamin
A in a variety of actions.

1.1. Vitamin A Transport to the Brain

Diet-derived vitamin A, which is stored as retinyl esters in the liver, is released in a homeostatically
VAD:
vitamin A deficiency controlled fashion to provide a constant source of retinol to cells of the body, including those of the
brain. Retinol transport through the blood-brain barrier (BBB) is restricted (116). Levels of retinol
and retinyl ester are higher in the brain than in other tissues dependent on retinol, such as skin and
testis, and are similar to levels in adipose tissue in the mouse (71). By contrast, other studies do not

248 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 show that vitamin A levels in the brain are higher than those in, for instance, the kidney (95, 130).
Nevertheless, levels in the brain are generally robust, and one study described high levels of retinol
in the rat brain with major differences between the sexes (6). Cerebrospinal fluid (CSF), which,
RA: retinoic acid
among other functions, transports factors within the brain, contains the same protein duo carrying
retinol in plasma, retinol-binding protein 4 (RBP4) and transthyretin (TTR), both of which are RAR:
retinoic acid receptor
synthesized by the CSF-generating tissue, the choroid plexus (33, 36). RBP4 is also present in
epithelial cells of the blood vessel walls in the brain that make up the BBB (98). The choroid RXR:
plexus also expresses the protein that binds to retinol-bound RBP4 and assists in transporting retinoid X receptor
retinol into the cell, stimulated by retinoic acid 6 (STRA6), the knockout of which greatly reduces
retinol content in the brain (76). Retinol can also enter cells through passive diffusion aided by
the presence of cellular retinol-binding protein 1 (CRBP1) in the cell. CRBP1 is present in the
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choroid plexus (98) and blood vessel walls in the brain (161), capturing retinol and increasing its
influx across the BBB. Note that RBP4 also has a wider distribution in certain brain subregions,
implying a role for RBP4 in transporting retinol within the brain itself (19, 52, 80).
Annu. Rev. Nutr. 2020.40:247-272. Downloaded from www.annualreviews.org

1.2. Vitamin A Function in the Cell

Retinoic acid (RA) is the key to vitamin A and brain function because, for most functions,
it is the active metabolite of vitamin A (the steps of vitamin A metabolism are illustrated in
Figure 1). Indeed, the brain is exceedingly efficient at generating RA compared with other vi-
tamin A–dependent organs (155). Cellular retinoic acid–binding protein 1 and 2 (CRABP1 and
CRABP2) maintain solubility of RA, and CRABP2 in particular plays a role in transporting RA
into the nucleus (110). RA carries out its primary role in the nucleus, binding to specific retinoic
acid receptors (RARs), α, β, or γ, members of the nuclear receptor family of transcriptional regu-
lators (10). RARs are activated by all-trans and 9-cis isomers of RA and function as heterodimers
with the nuclear retinoid X receptor (RXR) subtypes α, β, and γ. RXR is a RA receptor activated
by 9-cis RA and potentially other endogenous retinoids (83). In general, retinoids refer to the
naturally occurring and synthetic analogs of vitamin A. The RAR-RXR heterodimer regulates
gene expression by binding to a retinoic acid response element (RARE) of the promoter of target
genes. Both types of receptors are present in the central nervous system (CNS), and protein ex-
pression has been thoroughly investigated by Kreżel
˛ et al. (82). In the adult brain, RARα and RARγ
are widely distributed, with high protein levels present in both the hippocampus and the cortex,
whereas RARβ, RXRα, RXRβ, and RXRγ display a restricted presence (82). In these restricted
regions, however, levels can be high; for example, RARβ is strongly expressed in the striatum and
hypothalamus (82). The local expression of RAR proteins does not always match that of their mes-
senger RNA (mRNA) transcripts, implying a crucial role for posttranscriptional control in their
expression. RA via the RARs has the potential to regulate hundreds of genes directly or indirectly
(8, 85). The system is turned off predominantly by the CYP26 group of the cytochrome P450
family of enzymes (141), in particular CYP26B1 (1, 141).

2. THE NEED FOR VITAMIN A AND RETINOIC ACID IN THE

HIPPOCAMPUS TO CONTROL NEUROPLASTICITY
ESSENTIAL FOR LEARNING AND MEMORY
2.1. Control of Retinoic Acid Synthesis in the Hippocampus
The hippocampus, which is part of the limbic system, is a key site involved in cognition owing to
its role in learning and memory (13). It is a highly plastic brain region; it can adapt and change

www.annualreviews.org • Retinoic Acid and Cognition 249

 Homeostatic
synaptic plasticity
13 14
GluR1
RARα mRNA RA FMRP
RNA granule
16
GluR1
15 mRNA
Translation
Dissociation
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RARα RA

1
uR
17

Gl
Insertion
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Glutamate
Glutamate
1 7
3 18
Dendritic
TTR RBP4 Retinol STRA6 Retinaldehyde CRBP1 Diffusion to spine
RA neighboring
RA

5 cells
LD
0

6
H1

2 8
H
D

9
RD
RR

RA CRABP1/ Axon
CRABP2
4 Genomic 12 RA terminal
CRBP1 Retinol actions 10 RA
RA 19 Nongenomic
11 actions
RAR/RXR Catabolism
RARE CYP26
4-oxo
RA

Figure 1
A schematic of vitamin A metabolism in the cell. (Step 1) Retinol is delivered to neurons by the RBP4/TTR complex and can enter the
cell via (Step 2) free diffusion or via (Step 3) STRA6. Once inside the cell, (Step 4) retinol binds to CRBP1. (Step 5) It can then be
metabolized to retinaldehyde by retinol dehydrogenases (e.g., RDH10). This step is reversible and retinaldehyde can be (Step 6)
metabolized back to retinol by RRD. (Step 7) Retinaldehyde, bound to CRBP1, can be (Step 8) converted to RA by RALDH1, RALDH2,
and RALDH3, which are encoded by the genes ALDH1A1, ALDH1A2, and ALDH1A3, respectively (75). Inside the cell, (Step 9) RA is
bound to CRABP1/CRABP2 to maintain solubility of RA, and (Step 10) CRABP2 in particular plays a role in transporting RA into the
nucleus (110). (Step 11) RA exhibits genomic functions through activation of transcription in the nucleus by binding to RA receptors
(RAR-RXR heterodimers) (10). (Step 12) RA can also exhibit nongenomic functions, such as (Step 13) its involvement in HSP. (Step 14)
RARα in the cytoplasm is present in mRNA granules, where it binds the mRNA of an ionotropic glutamate receptor subunit (GluR1,
which is a subunit for the AMPA-type receptor). (Step 15) When RA binds to RARα, GluR1 mRNA disassociates, and in the presence of
FMRP it becomes available for (Step 16) translation and (Step 17) insertion into the membrane. Alternatively, RA (Step 18) can diffuse to
neighboring cells or (Step 19) is removed by catabolism to 4-oxo RA by CYP26A1, CYP26B1, and CYP26C1, with CYP26B1 the
predominant form in the brain (1, 141). Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CRABP1, 2,
cellular retinoic acid–binding protein 1, 2; CRBP1, cellular retinol-binding protein 1; FMRP, fragile X mental retardation protein;
GluR1, glutamate receptor 1; HSP, homeostatic synaptic plasticity; mRNA, messenger RNA; RA, retinoic acid; RALDH, retinaldehyde
dehydrogenase; RAR, retinoic acid receptor; RARE, retinoic acid response element; RXR, retinoid X receptor; RBP4, retinol-binding
protein 4; RDH10, retinol dehydrogenase 10; RRD, retinal reductase; STRA6, stimulated by retinoic acid 6; TTR, transthyretin.

250 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 function in response to the environment. RA is often associated with, and regulates, regions of
high neuroplasticity (135). RA signaling in the hippocampus is regulated by the availability of its
synthesizing and catabolizing enzymes. In mice, a gradient of RA exists across the infrapyramidal
LTP: long-term
and suprapyramidal blades of the hippocampal dentate gyrus (52) set up by strong expression of potentiation
RALDH1- and RALDH2-synthesizing enzymes in the meninges and the presence of a CYP26B1-
LTD: long-term
catabolizing enzyme between the blades. This gradient in RA signaling across the dentate gyrus
depression
contributes to higher cell proliferation in the infrapyramidal versus suprapyramidal blades. It can
be disrupted by inhibition of CYP26B1, resulting in a ratio of cell proliferation between the in-
frapyramidal and suprapyramidal blades that is closer to 1 (141). That these two blades process
information differently likely plays a role in a refined aspect of learning termed pattern separation,
and control of cell proliferation and generation of new neurons (neurogenesis) may be incorpo-
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rated into this type of learning (129). Astrocytes, which provide structural and functional support
to surrounding neurons (102), are another potential source of RA for the hippocampus and are
the most abundant glial cells in this region. In vivo, astrocytes express low levels of retinaldehyde
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dehydrogenases (RALDHs); however, in the event that the availability of retinol is low, they can
increase protein expression of RA-synthesizing enzymes (133). Astrocytes synthesize and release
RA to neurons in a paracrine manner (151). Hippocampal neurons themselves are also proposed
to have an activity-controlled autocrine system of synthesis (3). A recent study showing the capac-
ity of RA to correct age-related cognitive decline suggests that the blood directly supplies RA to
the hippocampus (37).
As with much of the initial studies of vitamins, the first phase of research on the brain and
vitamin A came from studies of VAD in the adult animal. This approach provided the earliest
evidence that vitamin A affects cognition, recognizing, however, that VAD broadly impacts the
whole animal, not just the brain. Further, studies of VAD determine the action of not only RA
but also vitamin A, because although most effects of vitamin A occur via RA (106), the signaling
pathway induced directly by retinol when bound to RBP4 via STRA6 (111) may also influence
the brain, which has been little investigated. Studies of VAD in mice are cumbersome because
this species has a high capacity for vitamin A storage and induction of VAD requires a prolonged
period, up to 40 weeks (40). However, time to deficiency can be shortened by early depletion
starting at day 10 of pregnancy (138). Thus, high-quality VAD experiments require a thoughtful
understanding of vitamin A biology.

2.2. Retinoic Acid and Neuroplasticity in the Hippocampus: Long-Term

Potentiation, Long-Term Depression, and Neurogenesis
Vitamin A is essential for two aspects of neuroplasticity long considered key to learning and mem-
ory: long-term potentiation (LTP) and long-term depression (LTD). These processes are the cel-
lular responses that induce lasting changes in synaptic strength, leading to strengthening or weak-
ening of neuronal circuits. The synapse provides the link between each neuron in the circuit, and
changes in neuronal circuits are believed to form the substrate of learning and memory. Changes in
synaptic strength are quantified by measuring postsynaptic electrical events, which involves mea-
suring the postsynaptic currents (PSCs) that reflect the current passing via cellular ion channels
(see the sidebar titled Ion Channels and Neuronal Activity).
VAD in rodents impairs both LTP and LTD in the hippocampus, and the degree of their
disruption correlates with the level of retinol deprivation (105). These impairments can be rescued
by applying RA or boosting dietary retinol. VAD further compounds the decline in RA signaling
because such conditions lead to a decrease in the expression of RARs (RARβ and RXRβ/γ) (40).
VAD affects another aspect of neuroplasticity important for learning and memory: neurogenesis.

www.annualreviews.org • Retinoic Acid and Cognition 251

 ION CHANNELS AND NEURONAL ACTIVITY
Postsynaptic currents can be either excitatory (EPSCs), in which the postsynaptic cell is more likely to fire an
action potential, or inhibitory (IPSCs), in which the postsynaptic cell is less likely to fire. Miniature postsynaptic
currents (mEPSCs and mIPSCs) are spontaneous events recorded in the presence of the action potential blocker,
tetrodotoxin. Neurons are equipped with different receptors, such as ionotropic glutamate receptors, that function
as ion channels and facilitate the activity of these cells. These include N-methyl-d-aspartic acid (NMDA), α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors. NMDA receptors are permeable to
calcium. Glutamate receptor 1 (GluR1)-subunit-containing AMPA receptors are permeable to calcium, sodium,
and potassium, whereas GluR2-subunit-containing AMPA receptors are impermeable to calcium. Kainate receptors
are permeable to sodium and potassium. These receptors facilitate the excitation of the cell. By contrast, chloride-
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permeable receptors responding to γ-aminobutyric acid (GABAA ) are inhibitory. The glutamatergic and GABAergic
receptors work together to balance neuronal activity in the brain to enable cognition.
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Bonnet et al. (16) showed that prolonged (>10 weeks) VAD causes decline in neurogenesis, cell
survival, and differentiation in the dentate gyrus likely via RA depletion, because RA is necessary
for early neuronal differentiation in the adult (66). VAD-induced decreases in the expression of
RARs, neurogenesis, and neuronal differentiation lead to spatial memory impairments that can be
reversed by RA supplementation (16, 25, 66).
An alternative, non-RAR-mediated route for RA action on neurogenesis may be signaling
through cytoplasmic binding proteins. CRABP1 can regulate cell properties by stimulating the ex-
tracellular signal-regulated kinase 1/2 (ERK1/2) (154). RA bound to CRABP1 activates ERK1/2,
which affects the cell cycle by slowing proliferation and preparing stem cells for differentiation
(94). Mice lacking CRABP1 display increased proliferation of neural stem cells in the hippocampus
and thus neurogenesis (94). These animals display improved learning and memory performance
when tested on novel object recognition and spatial memory tasks.
The ideal balance of RA is evidently crucial for normal cognitive function, as an excess of RA
can also result in impaired learning and memory. Treating mice with RA decreases cell prolif-
eration and neurogenesis and leads to spatial memory deficits (28). RA given chronically to rats
causes declarative memory impairments but in higher doses enhances the long-term retrieval of
implicit/procedural memory (35). These results suggest an optimal level of RA in the brain is
required to maintain normal cognitive function, and deviation from this level impairs cognition.
However, circumstances may exist or arise in the normal animal in which the level is too low and
increased amounts of RA will improve performance. Note that levels of RA in the brain are main-
tained locally and vary between areas; thus, such effects may be regional. Even relatively short
distances, such as between the infrapyramidal and suprapyramidal blades of the dentate gyrus,
display a RA gradient (52).
Studies of VAD have been further refined in genetically modified animals (knockout mod-
els), in which specific steps in the RA signaling pathway are blocked. For example, RARβ and
RARβ/RXRγ knockout mice are viable and phenotypically similar to wild-type animals but show
deficits in spatial memory tasks, and their learning does not improve during acquisition phase (23).
The same RARβ and RARβ/RXRγ knockout animals also display nearly complete loss of LTP and
LTD in the CA1 region of the hippocampus, even though their synapses appear structurally and
functionally normal (23). RXRγ single null mutant mice exhibit a selective and total deficit in LTD,
whereas their LTP is unchanged. Despite the changes in LTD, spatial memory in these animals re-
mains intact (23). Working memory is a type of short-term memory that allows temporary storage

252 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 and manipulation of information. Spatial working memory is tested using spontaneous alternation
in the Y maze, in which an animal must remember which arm of the maze was previously visited.
This contrasts, for instance, with recognition working memory, which is tested by determining
HSP: homeostatic
whether an animal recognizes a novel object that has not been previously presented to them in a synaptic plasticity
novel object recognition test. The RXRγ single null and RARβ/RXRγ double null mutants show
deficits in working memory tests (104, 156). Additionally, studies of the RARβ/RXRγ knockout
mice showed that these receptors are important for long-term declarative (conscious) memory,
which reflects cognitive flexibility (an ability to change from one learned response to another)
(104).
Studies of knockouts have been further refined through the use of conditional knockouts. The
selective ablation of RARα from layer 5 pyramidal neurons of the somatosensory cortex has re-
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vealed that this receptor is required for normal tactile sensory function (117). Mice recognize
different textures by use of their whiskers. Deletion of RARα impairs whisker-dependent discrim-
ination of texture (117). The authors of this study have also shown that RA maintains stable and
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mature dendritic spines, as conditional RARα knockout animals display increased elimination of
them. The formation of dendritic spines is another aspect of neuroplasticity because these are the
points on dendrites where the axons from other neurons make their synaptic contact (Figure 1).
The same study also found that RARα is required for experience-dependent spine remodeling
(117).

2.3. Retinoic Acid and Neuroplasticity in the Hippocampus:

Homeostatic Synaptic Plasticity
Homeostatic synaptic plasticity (HSP) (see the sidebar titled Homeostatic Synaptic Plasticity) is
another type of plasticity at the synapse that is dependent on RA and crucial for learning and
memory. The process of strengthening or weakening the synapse to stabilize firing and maintain
homeostasis is known as synaptic scaling (146).
Integral to RA’s involvement in HSP is the interrelationship of RA with intracellular calcium,
the concentration of which determines neuronal activity. Many studies have investigated the
interaction between calcium, calcium-related and calcium-dependent proteins, and RA. For
instance, rats on a VAD diet for 52 days display excessive calcium accumulation in the brain
(121). Importantly, calcium also feeds back on RA. Wang et al. (152) applied a calcium channel

HOMEOSTATIC SYNAPTIC PLASTICITY

Changes to the neuronal environment are essential for learning and memory. These changes are rapid and rely
on the specific adaptation of individual synapses [long-term potentiation (LTP) and long-term depression (LTD)].
Homeostatic synaptic plasticity (HSP) allows neurons to adapt to such a dynamically changing environment (54).
In this form of plasticity, the strength of a neuron’s synapses is finely tuned, which leads to the stabilization of
neuronal networks through alterations to negative feedback loops (93, 146). Neurons are equipped with calcium-
sensing mechanisms that allow them to recognize changes in activity and maintain functional stability (146). One
form of this maintenance is receptor trafficking and insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA)-type glutamatergic receptors into the postsynaptic plasma membrane (146). HSP changes neuronal
excitability, the strength of synapses, and the number of their contacts and includes spine remodeling (18, 30, 53,
117). HSP provides spatial and network-specific control of neuronal firing and finely tunes the excitation–inhibition
balance, preventing overexcitation in the form of runaway LTP (74, 119).

www.annualreviews.org • Retinoic Acid and Cognition 253

 blocker (nifedipine) or calcium chelators and saw an increase in the synthesis of RA, which
could be inhibited by N,N-diethylaminobenzaldehyde, an inhibitor of RA synthesis. These
experiments showed that the synthesis of RA is suppressed by intracellular calcium and stim-
GABA:
γ-aminobutyric acid ulated when calcium concentrations are low (3, 22). A calcium-binding phosphatase relevant
to the interaction between calcium and RA in neural cells, and crucial for HSP, is calcineurin.
Inhibition of calcineurin supports RA production (4). Prolonged blockage of calcineurin activity
in cultured hippocampal organotypic slices with cyclosporine A increases miniature excitatory
PSC amplitudes and decreases miniature inhibitory PSC amplitudes. These changes happen
through stimulation of RA synthesis and activation of RARα (4).
With the discovery of calcium control of RA synthesis came the integration of RA into HSP.
The entire pathway of HSP can be summarized as follows: (a) If neuronal activity is reduced,
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then intracellular calcium levels fall, which stimulates synthesis of RA. (b) RA is then available to
act on its targets and activate downstream pathways, including induction of translation of specific
calcium-permeable receptors. (c) RA-induced increase in calcium-permeable receptors increases
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passage of calcium into the cell. (d ) Rising intracellular calcium concentration halts RA synthesis
and thus stabilizes neuronal activity.
RA increases the expression of calcium-permeable receptors in this system via RARα. It does
not involve its typical function, regulating gene transcription, but instead involves the rapid action
of RARα in the cytoplasm to regulate protein translation and thus is nongenomic. RARα is actively
transported to the dendrites, where it acts as an mRNA-binding molecule, holding and blocking
the translation of mRNA such as that of glutamate receptor 1 (GluR1), a crucial subunit of the
AMPA receptor calcium channel. When RA binds RARα, it induces a conformational change in
the receptor and the dissociation of GluR1 mRNA, making it available for translation (3, 118).
Newly translated GluR1-subunit-containing AMPA receptors are inserted into the postsynaptic
membrane, allowing transport of calcium into the cell, which ultimately strengthens the excitatory
synapse and shuts off RA synthesis, closing the loop of HSP (Figure 1).
That RARα controls activity by binding to GluR1 mRNA suggests that it may act with other
RNA-binding proteins. An RNA-binding functional regulator, fragile X mental retardation pro-
tein (FMRP), which is present in dendrites and the nucleus, is required for RA-induced protein
synthesis of GluR1 (139). Thus, in the presence of FMRP, translation of GluR1 mRNA and in-
sertion of AMPA receptors into the postsynaptic plasma membrane is possible. The RA-induced
insertion of GluR1-containing AMPA receptors occurs exclusively in the synapses that are actively
used (5). This RA-dependent increase of postsynaptic GluR1-containing AMPA receptors is medi-
ated through a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)
mechanism (5). The SNARE proteins are fusion proteins involved in the exocytosis (membrane
insertion) of AMPA receptors (70).
HSP involves not only strengthening of excitatory synapses but also weakening of inhibitory
ones. RA suppresses synaptic inhibition though the removal of γ-aminobutyric acid (GABAA )
receptors from the synapse (128). The process also requires RARα, and FMRP is required to
enhance endocytosis of these receptors. These functions of RA are crucial for the upregulation
of excitatory strength and the downregulation of inhibitory strength and affect the balance of
excitation and inhibition.

2.4. Retinoic Acid Regulates Cognition by Controlling the Neurotransmitter

Acetylcholine and Mammalian Target of Rapamycin
RARα not only controls glutamatergic and GABAergic function but also affects the cholin-
ergic system. Choline acetyltransferase (ChAT) is required to synthesize the neurotransmitter

254 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 acetylcholine (ACh) and is essential for memory encoding. Blocking muscarinic ACh receptors
impairs memory encoding and working memory, and stimulating nicotinic ACh receptors en-
hances new information encoding (56). Work on murine septal cell lines showed that RA, acting
AD:
on RARα, increases mRNA expression of ChAT and vesicular ACh transporter (VAChT), which Alzheimer’s disease
is important for the storage of ACh (11).
The action of RA on GluR1 expression also acts to modulate LTP, as part of the mechanism to
regulate HSP, in a pathway that additionally involves mammalian target of rapamycin (mTOR).
Conditional knockout of RARα in the CA1 region of the hippocampus resulted in overstimulated
(runaway) LTP brought about by the enriched environment (59). RARα is presumed to normally
act to prevent this overstimulation, first by repressing GluR1 translation and then by repressing
mTOR signaling, which would otherwise also increase expression of GluR2, a second subunit of
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the AMPA receptor (59).

3. INVOLVEMENT OF VITAMIN A AND RETINOIC ACID

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IN COGNITIVE DISORDERS
Given the role of RA to support multiple essential pathways necessary for cognition in the brain,
it would be expected that disruption in RA signaling would be involved in neurological diseases
with clinical characteristics that include neurocognitive disorder. Neurocognitive diseases present
cognitive impairment when compared with the level of cognitive function prior to disease and can
include delirium, mild cognitive impairment, and dementia. The severity of the disease is assessed
by impairment in one or more principal cognitive functions, including learning and memory,
complex attention, perceptual-motor function, language, social cognition, and executive function
(126). Disorders including autism, schizophrenia, and Alzheimer’s disease (AD) disrupt cognition
at different life stages; for instance, autism starts in infanthood, whereas schizophrenia is more
likely to start around adolescence and AD occurs later in life. Irrespective of when these disorders
start, all have been linked with changes in RA signaling.

3.1. Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that usually starts before age
3 and lasts throughout life. It is characterized by stereotypical restricted and repetitive behaviors
or interests and by deficits in social interaction and communication (55). A variety of conditions,
including metabolic imbalance, multiple nutritional deficiencies, and increased levels of serotonin
[5-hydroxytryptamine (5-HT)] in serum, are reportedly linked to autism (55). Among these con-
ditions, vitamin and mineral deficiencies, including deficiencies in vitamins A, E, and D, calcium,
and folate, are more common in children with autism than in other children (55). The developing
brain is particularly sensitive to VAD because RA is required for CNS development (68, 99). As
discussed in Section 2, VAD during postnatal development in rats results in cognitive impairment
due to downregulation of RARα; reduced expression of the N-methyl-d-aspartic acid (NMDA)
receptor subunit NR1, which leads to the inhibition of neuronal calcium excitability; and de-
creased LTP in the hippocampus (68). In addition, VAD in rats during embryonic and postnatal
stages results in lower levels of histone acetylation due to the dysregulation of the cAMP response
element-binding protein (CREB)-binding protein, a histone acetyltransferase regulated by RARα
that contributes to impairment of spatial learning and memory in adulthood (58). A 2018 study
(55) of 33 children with autism showed that administration of a single dose of a vitamin A sup-
plement (200,000 IU) significantly increased retinol concentrations in serum, enhanced RARα
and RARγ mRNA expression levels in white blood cells, decreased 5-HT levels in serum, and
decreased tryptophan hydroxylase 1 expression necessary for 5-HT synthesis. The same study

www.annualreviews.org • Retinoic Acid and Cognition 255

 found that the Childhood Autism Rating Scales (CARS) score significantly increased approxi-
mately 6 months after vitamin A was administered compared with scores from 32 healthy chil-
dren in the control group (55). Considering that vitamin A levels are negatively associated with
DRD2: dopamine
receptor D2 the CARS score (the lower vitamin A levels are, the more severe ASD is) (96) and that the 5-HT
system plays a crucial role in sensory development, social behavior, and cognitive flexibility (55),
vitamin A supplement therapy as an adjunct to other routine medications could help patients with
autism with many aspects of behavior, including cognition.

3.2. Schizophrenia and Schizoaffective Disorders

Schizophrenia is a severe neurodevelopmental disorder characterized by affective and psychotic
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positive symptoms as well as negative symptoms that eventually result in cognitive and functional
impairments (see the sidebar titled The Basics of Schizophrenia). Genetic and environmental fac-
tors over the life course contribute to the development of schizophrenia (90, 108). The volume
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and morphology of different brain regions are affected by the disease (85, 88), and the wide range
of brain regions that are affected is one reason for the general acceptance of a neurodevelopmental
component to the disease (113). One of the first suggestions that RA is involved in schizophrenia
was in 1995 by Goodman (49), who proposed a retinoid dysregulation hypothesis. This hypothesis
linked RA signaling with schizophrenia on the basis that (a) the chromosomal loci of the genes
associated with schizophrenia overlap with loci of the genes of RA signaling, (b) dysregulation
of the RA signaling pathway induces congenital anomalies similar to those observed in patients
with schizophrenia, and (c) RA regulates the transcriptional activation of genes associated with
schizophrenia, including dopamine receptor D2 (DRD2) (50).
The strongest evidence supporting the first part of this hypothesis comes from a recent study
by Reay et al. (122). They used genome-wide association studies of the Psychiatric Genomics
Consortium to determine that common variants associated with schizophrenia were aggregated
with retinoid genes (122). Further, from the study of the Australian Schizophrenia Research Bank,
the authors found that rare variations in RARβ were linked with reduced cerebellar volume in
the subtype of patients with schizophrenia with severe cognitive deficits (122). In addition, rare
variations in RAREs proximal to genes regulated by RA were associated with schizophrenia (122).

THE BASICS OF SCHIZOPHRENIA

The onset of schizophrenia symptoms develops in either late adolescence or early adulthood (114). Schizophrenia is
characterized by a set of core features. Positive symptoms tend to relapse and remit (psychotic symptoms associated
with loss of contact with reality, e.g., visual and auditory hallucinations and delusions, and thought and perceptual
disturbances) and are associated mainly with hyperactivity of the mesolimbic dopaminergic pathway, which begins
at the ventral tegmental area (VTA) and ends in the ventral striatum. Negative symptoms (reduction in expression,
emotions, and motivation; impairment in spontaneous speech; and social isolation and withdrawal) and cognitive
impairment (a wide range of cognitive dysfunction that varies across individuals) are related to hypoactivity of the
mesocortical dopaminergic pathway, which begins at the VTA and ends in the prefrontal cortex (114). Both nega-
tive and cognitive symptoms are chronic (114). A recent review suggested that striatal hyperdopaminergia, either
through dysregulation of cortical dopaminergic systems or by disruption of signaling between the associative stria-
tum and frontal cortex, results in cognitive impairments (103). Abnormalities in cortical inhibitory γ-aminobutyric
acid (GABA)ergic neurons also have a key role in the pathophysiology of schizophrenia, resulting in emotional and
cognitive impairments (31).

256 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 The second part of the retinoid dysregulation hypothesis arises from the neurodevelopmen-
tal hypothesis of schizophrenia and the finding that abnormal fetal development results in fragile
brain function that, together with disruption to the CNS later in life, leads to schizophrenia (109).
PFC: prefrontal cortex
In particular, dysregulation of the striatal dopaminergic pathway is common to many of the risk
factors linked to schizophrenia (109). RA has a key role in embryonic and postnatal forebrain
development (84). Dysregulation in neuronal circuitry and function in the forebrain is associ-
ated with cognitive impairment in schizophrenia (84). Aldh1a3 mutant mouse embryos show a
reduction in DRD2 in the nucleus accumbens (21). They also show a decrease in the GABA-
synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) and a failure of the lateral gan-
glionic eminence progenitors to differentiate into GABAergic striatal projection neurons or of
GABAergic interneurons to migrate to either the cortex or the olfactory bulb (21). Reduction in
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GAD67 mRNA, along with alteration in GABAergic activity, is one of the most consistent findings
in postmortem schizophrenic dorsolateral prefrontal cortex (PFC) (31). A subtype of GABAergic
inhibitory interneurons that express the calcium-binding protein parvalbumin (PV) regulates ex-
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citatory and inhibitory balance as well as neuronal synchrony and has pivotal roles in higher cog-
nitive functions (87, 157). Impairment in GAD67 gene expression has been suggested to be limited
to the PV-containing GABAergic neurons (32). Abnormalities in these neurons result in develop-
mental brain disorders, including autism and schizophrenia (87). In this case, the impact of RA on
these neurons may be via control of postnatal rather than embryonic development, because RA can
regulate the development of early postnatal PV neurons in the medial PFC. The RA-degrading
enzyme CYP26B1 expressed in the thalamus is essential for these inhibitory interneurons to de-
velop normally in a regionally and temporally specific manner (87). Given the importance of RA in
forebrain development, it is unsurprising that a large population-based birth cohort study showed
that women in their second trimester who had less than 20 μg/dL retinol in their serum showed an
increased risk of schizophrenia and schizophrenia spectrum disorders in their offspring by more
than threefold (9). Thus, RA signaling has a regulatory effect on both embryonic and postnatal
development of GABAergic neurons in the PFC, where abnormal function has been linked to
schizoaffective and cognitive disorders.
The last part of the retinoid dysregulation hypothesis proposes that RA regulates the tran-
scriptional activation of genes associated with schizophrenia. A series of neurotransmitter sys-
tems, including dopamine, serotonin, GABA, ACh, and glutamate, are disrupted in schizophrenia
(140, 159). Several genes and molecules associated with the normal function of these neurotrans-
mitters are acted upon by RA signaling pathways, including dopamine, dopamine receptors, and
many other neurotransmitters and metabolic enzymes (50, 85, 90). Dopamine regulates various
physiological functions and behaviors, from reward-motivated systems to body movement to hor-
mone synthesis and secretion. Dopamine exerts its function by interacting with five distinct G
protein–coupled receptors. DRD2, though, is associated primarily with schizophrenia, and the
only proven treatments for the disease are antagonists of DRD2; chlorpromazine and haloperi-
dol are long-lasting DRD2 antagonists, and clozapine is a transient DRD2 antagonist (131). Of
particular interest is the recent finding that the action of clozapine may be mediated in part by
increasing endogenous levels of RA (123). DRD2 is extensively expressed in the CNS, pre- and
postsynaptically, and particularly in the striatum, mesencephalic dopaminergic neurons, and pitu-
itary gland (127). It regulates both dopaminergic neurons and dopamine release (127). The DRD2
gene is directly regulated by RA via a RARE in its promoter (50, 127), while blocking dopamine
signaling in adult rats by chronic haloperidol treatment results in a small but significant increase
in mRNA levels of RARβ1-3 and RXRγ1, which are expressed predominantly in the striatum (86).
Thus, there is a mutual regulatory system between RA receptors and DRD2 in the striatum that
may impact cognitive function and schizophrenia.

www.annualreviews.org • Retinoic Acid and Cognition 257

 Several other RA-regulated genes, including retinoic acid–induced protein 1 (RAI1), have been
linked to schizophrenia (57). RAI1 acts as a transcription factor affecting cell growth, regulation
of cell cycle, embryonic neurodevelopment, and neuronal differentiation; it directly and indirectly
promotes gene transcription required for neuronal communication and circuit assembly (42). It
is expressed in both the nucleus and the cytoplasm, implying roles in addition to control of tran-
scription (42). In addition, RAI1 induces expression of brain-derived neurotrophic factor, which
promotes neurogenesis and has neuroprotective actions (57). The gene RAI1 is significantly over-
expressed in the cerebral cortex of patients with schizophrenia, bipolar disorder, and major de-
pression (57), and its levels of expression are associated with phenotype severity in patients with
schizophrenia as well as their response to antipsychotic medications (90). Two single-nucleotide
polymorphisms (SNPs), rs4925102 and rs9907986, in the 5 -upstream region of the RAI1 gene are
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binding sites for two transcription factors, deformed epidermal autoregulatory factor 1 homolog
(DEAF1), related to intellectual ability, and RARα-RXRα, respectively (42). Together, these two
binding sites are responsible for 30–40% of RAI1 mRNA expression variation in the temporal
Annu. Rev. Nutr. 2020.40:247-272. Downloaded from www.annualreviews.org

cortex and PFC (42). Furthermore, RAREs have been found in the RAI1 promoter (45). RAI1
and RAR are coexpressed in human hippocampal neurons; RARα and RARγ are present in the
nuclei and RARβ is present in both the nucleus and the cytoplasm, indicating the possibility of
functional cross talk between these transcription factors (45). Because the expression of RAI1 is
regulated by RA (45), the increase in RAI1 expression in patients with schizophrenia and bipolar
disorder might be an indicator of dysregulated RA signaling.
Changes in the level of substrate for RA, retinol, has also been linked to schizophrenia. Two
retinoid-transporting proteins, apolipoprotein E (APOE), which transports retinyl esters in chy-
lomicrons (14), and TTR in the CSF, are downregulated in patients with schizophrenia (150), and
TTR expression increased significantly after patients were treated with antipsychotic medication
for 2 months (150). Such changes have the potential to alter the amount of retinol delivered to
cells in the brain and hence the amount of RA generated. In addition, SNP genotyping of seven
genes associated with RA function showed an association of two SNPs in ALDH1A2 (which en-
codes RALDH2) in Chinese patients with schizophrenia (149), and microarray results showed
ALDH1A1 (which encodes RALDH1, a protein strongly expressed in dopaminergic neurons) was
significantly reduced in patients with schizophrenia (51). This finding may suggest a connection
between RA signaling and schizophrenia, although RALDH1 is also involved in synthesizing neu-
rotransmitters, including GABA (79), and metabolizing catecholamines, including dopamine and
norepinephrine (2). A postmortem study showed twofold-greater expression of RARα in the den-
tate gyrus of a schizophrenic brain than in that of the control (51, 124). This increase might com-
pensate for the reduction in RA-synthesizing enzymes and an alteration to increase brain sensitiv-
ity to RA and might contribute to the upregulation of DRD2 and thus schizophrenia symptoms.
The association between RA and schizophrenia has led to the proposed use of retinoids to treat
disease. Bexarotene is a third-generation RXR-selective retinoid and an FDA-approved antitumor
agent used to treat advanced-stage cutaneous T cell lymphoma, lung cancer, and breast cancer (90).
Besides its genomic action, it can function nongenomically to rapidly regulate phosphoinositide
3-kinase and ERK1/2, promoting neurite outgrowth (90). In two clinical studies, bexarotene was
administered as an adjuvant agent (75 mg/day) together with ongoing treatment with antipsy-
chotic medication for patients with chronic schizophrenia (91, 92). In both studies, the total Posi-
tive and Negative Syndrome Scale scores improved, while positive symptoms reduced without any
improvement in negative symptoms (91, 92). Amelioration of positive symptoms might be due to
the promotion of synaptic plasticity by retinoids. These results show the potential therapeutic
effect of retinoids on the treatment of schizophrenia and schizoaffective disorders.

258 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 3.3. Age-Related Dementia and Cognitive Deficit
Age-related cognitive decline is a major health issue during the normal aging process. Loss of
synaptic plasticity in the hippocampus is considered a key part of cognitive impairment during GC: glucocorticoid
aging (37, 44). Both optimal macronutrients (proteins, fats, and carbohydrates) and micronutri-
ents (vitamins and minerals) can benefit cognition during aging (32). The key role of RA signaling
in memory is discussed in Section 2. Retinoid signaling in the brain declines with age, and the
cognitive deficits associated with aging can be reversed by treatment with RA (37, 41). Young
animals with VAD manifest cognitive deficits similar to those of aged animals, and these same
animals show downregulation of RARβ and RXRβ/RXRγ mRNA in their brain and hippocam-
pus (40). Age-related VAD in elderly subjects may be due to a change in vitamin A metabolism,
leading to a decline in retinol concentration in plasma (43). In rodents, the level of RA signaling
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activity is proportional to the expression of target genes associated with plasticity and memory per-
formance, including neurogranin (NRGN), protein kinase C substrate (RC3), and neuromodulin
(GAP43) (62). Animal models of VAD exhibit brain changes associated with aging, including a de-
Annu. Rev. Nutr. 2020.40:247-272. Downloaded from www.annualreviews.org

crease in hippocampal volume, neuronal dying and abnormal plasticity, loss of LTP and LTD, and
a reduction in neurogenesis, all of which are reversible by administration of RA (115). In addition,
a decrease in RA-mediated transcription in aged C57BL/6 mice disrupted hippocampal cellu-
lar pathways and functions necessary for long-term declarative memory and short-term/working
memory, whereas administration of a vitamin A supplement had a preventive action, likely through
RARβ and RXRγ as demonstrated by studies of RARβ/RXRγ knockout mice (104).
RA signaling indirectly modulates plasticity, memory, and cognition through glucocorticoid
(GC) pathways in the hippocampus (115), and changes in GC pathways may connect RA with
cognitive loss in aging and other disorders. Both mineralocorticoid receptors and glucocorticoid
receptors (GRs) are involved in this process. GC levels have an inverted-U-shape effect on cogni-
tion and plasticity and can induce age-related cognitive deficits through deficiency or chronic ex-
cess, eventually reducing hippocampal volume (115). Hyperactivity of the hypothalamic-pituitary-
adrenocortical (HPA) axis in VAD LOU/C rats has been reported, with an increase in total level
of corticosterone in plasma under both basal and stress situations by which RA treatment reversed
the condition to normal levels (101). By contrast, a chronic, high dose of RA administered to young
rats leads to an increase in HPA axis activity and in corticosterone in plasma (20); this could be
due to a derepressor effect of RARα on GRs [as explained by Hu et al. (60)]. Thus, abnormally
high or low levels of RA can dysregulate the HPA axis (115). RA can induce its regulatory effect
on GC levels in plasma and HPA axis activity through both the hypothalamus, regulating genes
including corticotropin-releasing hormone via RARα, and the pituitary gland, inhibiting adreno-
corticotropic hormone (115), and potentially through the adrenal gland (63, 101). Wistar rats with
VAD showed a reduction in corticosteroid-binding globulin, a plasma GC-binding protein, which
leads to higher free corticosterone in plasma in these rats. This in turn results in impaired hip-
pocampal neurogenesis, reduced spatial memory, and increased anxiety-like behavior (15). These
effects can be reversed by administration of RA (15). These VAD rats showed increases in 11β-
hydroxysteroid dehydrogenase 1 (11β-HSD1), the enzyme catalyzing regeneration of active GCs
from inactive forms, in the hippocampus (15). An increase in 11β-HSD1 can result in hyperactiv-
ity of the HPA axis and a decline in hippocampal plasticity, including inhibition of neurogenesis
and impairment in spatial memory (15), presumably due to higher GC levels in the hippocampus
(15). In this same system, administration of RA for 1 month normalizes excess GC and memory
impairment (15). This normalization of excess GC may occur because RA can negatively regulate
11β-HSD1 expression and activity, which has been shown in differentiated C2C12 myotubes (7).
In summary, there is a strong relationship between GCs, RA, and cognition; RA may be important

www.annualreviews.org • Retinoic Acid and Cognition 259

 to maintain optimal GC levels throughout the life span and particularly during aging to prevent
memory and cognitive decline. Administration of RA may reduce the negative effects on memory
and cognition by GC dysregulation during aging.

3.4. Alzheimer’s Disease

AD is a neurodegenerative disease characterized by two pathological hallmarks within the brain:
amyloid plaques and neurofibrillary tangles. These are caused by the formation and deposition of
insoluble forms of synaptotoxic amyloid β (Aβ) peptides and neurotoxic hyperphosphorylated tau
protein, respectively (47, 120, 132). These abnormal accumulations eventually lead to cognitive
impairment. Most cases of AD are sporadic; however, familial AD is associated with gene mutations
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that favor formation of amyloid plaques and hyperphosphorylated tau.

Several studies suggest a relationship between AD pathophysiology and a reduction in RA
signaling. In rats, six months of VAD downregulates RARα and reduces ChAT expression, without
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neuronal loss, and this precedes the deposition of Aβ seen in animals deprived of vitamin A for 1
year (26). Patients with AD on a normal diet had lower concentrations of retinol in plasma than
did age-matched controls on the same diet (17). Suggestive that RA signaling itself may fall in AD
is that RARs declined in five animal models of AD at early stages of disease (78). One mechanism
by which RA signaling may fall in AD is through Aβ inhibition of RA synthesis (107).
Thus, if RA decline is associated with AD, then reduction in RA signaling may contribute to
some of the hallmarks of the disease. Several in vitro studies indicate that genes associated with
β-amyloid precursor protein (APP) processing and decreased amyloid plaque formation are reg-
ulated by RA (34, 78, 85). As a result of these studies, RA and its related compounds have been
proposed as therapeutics for AD. Retinoids can decrease formation of Aβ from APP by increas-
ing the expression and activity of the α-secretase ADAM10 (a disintegrin and metalloproteinase
domain-containing protein 10) (136), the pathway shown in Figure 2. ADAM10 mRNA levels in-
crease after application of RA to neuroblastoma cells (136). Another way in which retinoids may be
therapeutic for AD is by preventing formation of Aβ fibrils. Vitamin A can inhibit oligomerization
of Aβ40/Aβ42 in vitro (143). When treated with vitamin A, aggregated Aβ in human embryonic
kidney 293 cells were less toxic than intact Aβ fibrils and oligomers (143). A variety of retinoids
and β-carotene have antiamyloidogenic and fibril-destabilizing activity and could prevent Aβ fibril
formation in a dose-dependent manner in vitro (112).
Several ligands of RAR and RXR have shown promise in animal models of AD and in human
clinical trials (reviewed in 107). Acitretin, a RAR ligand (agonist), increased mature ADAM10,
promoting α-secretase activity and thus the nonamyloidogenic pathway in neuroblastoma cells,
leading to a two- to threefold increase in activity of α-secretase versus that of β-secretase (145).
RA reduces β-secretase trafficking and membrane localization through activation of protein ki-
nase C (81), thus inhibiting the amyloidogenic pathway. Administration of RA results in down-
regulation of β-site amyloid precursor protein–cleaving enzyme 1, acting through nuclear fac-
tor κB suppression, in the Tg2576 mouse model of AD (153). Intracerebral injection of acitretin
into the APPPS1-21 mouse model of AD results in reduction of Aβ40/Aβ42 (145). In a phase 2
clinical trial, administration of oral acitretin (30 mg/day) for 4 weeks increased sAPPα levels in
the CSF of patients with AD, implying an increase in nonamyloidogenic APP processing (39).
Tamibarotene (Am80), a RARα/RARβ ligand (agonist) used to treat relapsed acute promyelocytic
leukemia (107), reduced the level of insoluble Aβ40/Aβ42 in APP23 transgenic mice, a model of
cerebral β-amyloidosis and AD (72). In addition, coadministration of Am80 with the RXR ago-
nist HX630 to an AβPP23 mouse model of AD significantly reduced the insoluble Aβ peptide in
the brain and increased the learning ability of those animals. Furthermore, this coadministration

260 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 Positive effects of retinoic acid on AD
Neuronal function: Anti-inflammatory:
1) Neurogenesis (+) 1) Proinflammatory cytokine:
AD(–) 2) Neuroprotection (+) (IL-6 and TNF-α) (–)
3) Synaptic function (+)
AD(+)
Aβ clearance:
1 Aβ generation: 1) APOE (+)
RA-
2 1) ADAM10 (+) 2) IDE (+)
RA-
synthesizing degrading 2) α-Secretase (+)/β-secretase (–) 3) Neprilysin (+)
enzyme RA enzyme 3) Nonamyloidogenic pathway (+) 4) Phagocytosis (+)
TTR RBP4 Retinol
Retinol (CYP26) 4) Amyloidogenic pathway (–)
STRA6
4-oxo
3
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RA

trans-Golgi
network
RA
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Genomic AP
APP
5
RA actions
RAR/RXR
Nongenomic
RARE mRNA actions APP

RARα RA AD (–) 4 13
sAPPβ

22 13 6
RA (+) RA positive effect on pathways related to AD CTF89/99
RA (–)
RA (–) RA negative effect on pathways related to AD Endosome
β
12 AICD
D
11
AD (+) AD’s positive effect on RA signaling β-secretase P3
P
CTF89/
11
AD (–) AD’s negative effect on RA signaling 99 γ
15 10
Nonamyloidogenic pathway AICD
γ-secretase
γ
Amyloidogenic pathway 15 Aβ 14 CTF83
γ-secretase 7
Aβ-degrading enzymes 9
α sAP
sAPPα
Aβ-clearing enzymes
(neprilysin and insulin- Aβ monomer 8 9
degrading enzyme) secretion
α-secretase
Amoeboid microglia 21
Mitochondria Microglia and
Astrocyte 23 astrocytes
Proinflammatory RA (+)
RA (+)
response
Choline
transferase 16 IL-6
6
Acetyl-CoA Oligomerization 19 TNF-α Amyloid
IL-6 plaques TNF-α
Ch Aβ
AT RA (–)
CoA oligomers

ACh
IL-6
VAChT TNF-α
Synaptic
ACh vesicle 20
Aβ-clearing
RA (+) enzymes 18
Choline 17
ACh Aggregation
AChE
Cholinergic Fibrillization Aβ fibrils
Acetate receptor
Postsynaptic nerve
(Caption appears on following page)

www.annualreviews.org • Retinoic Acid and Cognition 261

 Figure 2 (Figure appears on preceding page)
Reduction of RA signaling pathways through decreasing availability of retinoids in AD. (Step 1) Decreasing RA-synthesizing enzymes
and (Step 2) increasing RA-degrading enzymes (e.g., CYP26) may help reduce RA bioavailability in AD, which (Step 3) dysregulates
gene expression normally controlled by RA (107). (Step 4) Furthermore, AD downregulates RARα in forebrain neurons. (Step 5) Aβ
peptide consists of 38–43 amino acids arising from proteolysis of a large transmembrane protein, APP, generated in the trans-Golgi
network. APP is processed by α-, β-, and γ-secretases (12). Two pathways can process APP: (Step 6) the nonamyloidogenic APP-
processing pathway and (Step 7) the amyloidogenic APP-processing pathway (24). In the nonamyloidogenic pathway, (Step 8)
α-secretase cleavage of APP within the Aβ domain results in production of (Step 9) long soluble sAPPα and CTF83, and (Step 10)
γ-secretase cleavage of CTF83 generates (Step 11) P3 and amino-terminal AICD (24). In the amyloidogenic pathway, (Step 12)
β-secretase cleaves APP within the Aβ domain, resulting in (Step 13) production of sAPPβ and CTF89/99 (24). (Step 14) γ-Secretase
cleavage of CTF89/99 generates (Step 15) neurotoxic Aβ40/Aβ42 peptides and the AICD (24). The ADAM family proteins regulate
α-secretase activity. BACE1 is considered a major brain β-secretase (24), and the activity of γ-secretase is based on a multiprotein
complex consisting of PS1 and PS2 (24, 85). The steps of Aβ formation occur in the endosomal compartment and subsequently
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exocytose to the extracellular region (24). Although proteases can cleave Aβ, the self-aggregation of the Aβ42 peptide leads to (Step 16)
oligomerization and (Step 17) fibrillization of Aβ fragments, deposition, and (Step 18) amyloid plaques that eventually result in AD
pathology (24). (Step 19) RA has antiamyloidogenic, fibril-destabilizing, and anti-inflammatory activities, and (Step 20) it increases Aβ
Annu. Rev. Nutr. 2020.40:247-272. Downloaded from www.annualreviews.org

clearance. Furthermore, RA promotes the nonamyloidogenic pathway and inhibits the amyloidogenic pathway through its respective
(Step 21) positive effects on α-secretase and (Step 22) negative effects on β-secretase activity. (Step 23) Finally, RA increases ChAT and
VAChT expression, which results in a rise in ACh availability in the synaptic cleft. Abbreviations: Aβ, amyloid beta; ACh, acetylcholine;
AChE, acetylcholine esterase; AD, Alzheimer’s disease; ADAM10, a disintegrin and metalloproteinase domain-containing protein 10;
AICD, APP intracellular domain; APOE, apolipoprotein E; APP, β-amyloid precursor protein; BACE, β-site amyloid precursor
protein–cleaving enzyme; ChAT, choline acetyltransferase; CoA, coenzyme A; CTF, carboxy-terminal fragment; IDE, insulin-
degrading enzyme; IL, interleukin; mRNA, messenger RNA; PS, presenilin; RA, retinoic acid; RAR, retinoic acid receptor; RARE,
retinoic acid response element; RBP4, retinol-binding protein 4; RXR, retinoid X receptor; sAPPα, secreted APPα; STRA6, stimulated
by retinoic acid 6; TNF-α, tumor necrosis factor α; TTR, transthyretin; VAChT, vesicular ACh transporter.

elevated the mRNA level of insulin-degrading enzyme (IDE) and neprilysin [also known as mem-
brane metallo-endopeptidase (MME)], which are Aβ-degrading enzymes, in vivo and increased
activity of microglia phagocytotic activity in vitro to clear Aβ (73). Bexarotene, an RXR agonist, is
also proposed as an AD therapeutic. Results suggest that it has a direct neuroprotective effect on
the 5xFAD mouse model of AD by repressing inflammation and astrogliosis, preventing neuronal
loss, increasing synaptic markers, and improving animal behavior (100). Bexarotene increased
APOE, which can mediate Aβ clearance, and the drug reduced Aβ accumulation in the APP/PS1
mouse model of AD (27). In addition, RXR activation promotes APOE and ATP-binding cas-
sette transporter subfamily A member 1, a major transporter required to regulate hemostasis of
cellular cholesterol and phospholipid, and through various routes stimulates proteolytic Aβ degra-
dation via extracellular IDE and microglial neprilysin (27, 67). Furthermore, bexarotene regulates
microglia phagocytosis of Aβ through upregulation of the phagocytic receptor CD36 (158). Treat-
ment with bexarotene (300 mg) for 30 days in a small clinical trial of 20 patients with AD with
APOE3 alleles showed a significant reduction in brain amyloid as well as a significant increase in
triglyceride levels in serum, resulting in cardiovascular risk (29). Unfortunately, due to poor pen-
etration of the BBB by bexarotene and to hypertriglyceridemia side effects, the outcome in the
clinical trials was not satisfactory (107).
Chronic inflammation and astrocytosis are among the histopathological features of AD and
are other routes by which retinoids may be therapeutic. Aβ-induced injury and plaque formation
trigger inflammatory and proinflammatory responses. Aβ plaques induce phagocytic responses
in microglia and they synthesize Aβ-clearing enzymes, including neprilysin and IDE, which play
crucial roles in the clearance of Aβ (48). By contrast, sustained inflammatory responses caused by
activated microglia are related to AD pathology; the proinflammatory cytokine tumor necrosis
factor α (TNF-α) is part of this response, which results in degeneration and prevention of Aβ

262 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 clearance (48). Neurons can also express both IDE and neprilysin to clear Aβ plaques (48). RA can
inhibit the production of the cytokines induced in AD inflammatory responses [e.g., interleukin 6
(IL-6) and TNF-α] via RARs expressed in cells mediating these responses (e.g., microglia and
astrocytes) (136). RA treatment of the MC3T3-E1 cell line or human lung fibroblasts strongly
suppresses IL-6; furthermore, it inhibits the production and expression of TNF-α and inducible
nitric oxide synthase in activated microglia in rat microglia cultures (136). RA can exert its anti-
inflammatory action on the CNS through glia cells: It lessens the release of neuroinflammatory
factors; switches the microglia from amoeboid (active form) to ramified (resting form); and acts
as a self-regulator, inducing expression of RA catabolic enzymes in microglia (136).
Changes to the cholinergic system are part of the pathophysiology of AD and are also potential
targets for RA. As mentioned in Section 2.4, the presynaptic level and function of ACh, an impor-
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tant neurotransmitter in learning and memory, decrease in AD (25, 46), leading to the cholinergic
hypothesis of AD. This hypothesis proposes that the reduction in ACh in the cerebral cortex and
other parts of the brain due to the loss and degeneration of cholinergic neurons leads to cognitive
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impairments in patients with AD (47). Increasing ACh levels in the synaptic cleft of the AD brain
is an accepted approach to slow down cognitive impairment. As discussed in Section 2.4, RA in-
creases gene expression of the ACh-synthesizing enzymes ChAT and VAChT, which make ACh
available for secretion at the nerve terminal (11). Reducing vitamin A in rats results in a fall in ACh
in the hippocampus and decreases nuclear size in neurons of the CA1 region of the hippocampus,
as well as reduces spatial learning (25). Scopolamine, a nonselective muscarinic antagonist, has
been used as a model for inducing amnesia in young, healthy experimental animals, and drugs that
reverse a scopolamine-induced cognitive deficit may be considered potential drugs for AD (47).
Synthetic RAR ligands (tamibarotene, Am555S, and Tp80) and an RXR ligand (HX630) reverse
the memory deficit induced by scopolamine in a passive avoidance paradigm (137). Therefore, RA
can promote both production and availability of ACh at the synapse as a mechanism by which it
may improve cognitive function in AD.

4. VITAMIN A AS A COGNITIVE ENHANCER

The concept that a nutritional supplement can act as a cognitive enhancer has existed for many
years, sometimes with dubious providence. Whether vitamin A is such a prodigious treatment
remains an open question. As discussed in Section 2.1, VAD (160) triggers disease with cognitive
loss, even in the case of marginal deficiency (160), and supplementation with vitamin A is certainly
beneficial in such cases. VAD may occur with normal aging (Section 3.3), although what deficiency
entails is more complex than on first consideration because it is not necessarily a homogenous
decline across the body. In rats, vitamin A levels in plasma fall with age but levels in local tissue can
rise, perhaps in compensation (147). In association with neurodegenerative diseases such as AD,
there is a local deficiency in RA signaling in the brain (Section 3.4). Disrupted vitamin A transport
may be a cause of local deficiency, and the high concentrations of the retinoid-binding proteins in
blood vessels of the brain and choroid plexus indicate the importance of retinoid transport across
the BBB and CSF (Section 1.1). It is vital to consider the movement of vitamin A when viewing
its relationship with brain function; for instance, APOE, the APOE4 polymorphism of which is
linked to AD, is crucial for clearing retinyl esters from the blood (65). VAD, when assumed to
mean deficiency throughout the body rather than at a specific region, is also problematic when
studying its effects in humans. At least in the very elderly, retinol concentrations in plasma do not
correlate with concentrations in the brain; thus, serum levels are not an effective determinant of
brain concentrations (144).

www.annualreviews.org • Retinoic Acid and Cognition 263

 Nonetheless, a few studies have found correlations between vitamin A intake and cognition.
For instance, low circulating levels of retinol potentially predict increased risk of cognitive decline
(61), whereas a carotenoid-rich dietary pattern may help preserve cognitive function during ag-
ing (77). Both serum and brain carotenoids correlate positively with cognitive measures (69, 97).
However, a systematic review by Rutjes et al. (125) of vitamin or mineral supplements for cognitive
improvement did not find evidence for the benefits of such supplements, although they suggested
there was a real but small signal of effect from long-term studies of antioxidant vitamins, partic-
ularly beta-carotene. Of note, in the very elderly, concentrations of plasma carotenoids, unlike
plasma retinol (see above), correlate with concentrations in the brain (144).
To conclude, vitamin A supplements do not have a major effect on cognitive improvement
in the normal adult, and any small effect may be due as much to antioxidant properties as to
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the promotion of retinoid signaling pathways. This finding may not be surprising under normal
circumstances, as systemic vitamin A is under robust homeostatic regulation and a diet high in
vitamin A would just increase storage and excretion and not increase RA signaling pathways above
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normal. It may be hypothesized, though, that the small effects observed by some studies may
represent a larger effect in a small population already depleted in vitamin A due to genetic or
nutritional reasons, and that if a personalized medicine approach were tailored to individuals with
VAD, the effect on cognition may be much greater.

5. CONCLUSION AND THE FUTURE

It has been realized only recently that vitamin A and RA are important for brain function and that
they were not among the early discoveries of VAD research because their effects are not lethal and
can require refined assays for their detection. However, these assays have revealed that vitamin A
and RA are crucial for supporting neuroplasticity necessary for learning and memory as well as
other cognitive processes. That the brain requires retinoids for these higher-order processes ex-
plains the high capacity of the brain to use even low levels of vitamin A through elaborate patterns
of retinoid-binding proteins to capture vitamin A and its efficient capacity to convert vitamin A
to RA to activate genomic and nongenomic pathways via regionally localized RARs. A common
theme apparent in neurodegenerative, neurodevelopmental, and several psychiatric diseases that
impact cognition is that the disrupted pathways that cause these diseases are among those neces-
sary for RA signaling. This helps explain the decline in neuroplasticity in these disorders and may
also explain changes in certain neurotransmitter pathways, including dopaminergic circuits us-
ing DRD2, in psychiatric diseases. The use of drugs targeted to RA receptors has shown promise
in rebalancing some of these pathways. Further activation of these receptors may suppress the
neuroinflammation evident in several of these disorders.
As a field still at a nascent stage, many questions about the roles of vitamin A and RA in the
control of cognition remain unanswered, and a better understanding of these roles may provide
important insights into the pathways used in particular cognitive processes. This includes vita-
min A’s involvement in higher-order cognitive functions and speech/language disorders evident
in people with FOXP2 mutations (89, 148). In quite a different direction, a prominent recent hy-
pothesis linking changes in gut microbiota with numerous diseases, including AD, proposes that
retinoid signaling is an intermediary (38). Finally, the hypothalamus is a hot spot in the brain for
RA signaling, mediating some elements of hypothalamic control of the endocrine system and ho-
meostasis in the body (134, 142). Tanycytes, which act as nutrient-sensing cells in the brain, are key
to RA function in the hypothalamus, and this finding opens the possibility that the hypothalamus
regulates vitamin A homeostasis in the body and the brain.

264 Wołoszynowska-Fraser • Kouchmeshky • McCaffery

 SUMMARY POINTS
1. Early research on vitamin A did not focus on the brain, and unlike, for instance, the
eye or reproductive system, the central nervous system does not cease to function when
vitamin A is deficient. This might be due in part to the high efficiency of the brain to
synthesize retinoic acid (RA).
2. Vitamin A and RA are crucial, however, for neuroplasticity and aspects of brain function
necessary for cognition.
3. The nongenomic action of RA to, for instance, control protein translation and activate
extracellular signal-regulated kinases may be routes of signaling in the brain that are just
as important as the traditional role of RA receptors to regulate transcription.
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4. Neurodegenerative diseases of the brain such as Alzheimer’s disease may result from a
local deficiency in RA signaling due to, for instance, a fall in RAR levels.
Annu. Rev. Nutr. 2020.40:247-272. Downloaded from www.annualreviews.org

5. Neurodegenerative, neurodevelopmental, and psychiatric diseases in which a fall in RA

function leads to a decline in cognition are possible targets for treatment by RA and its
analogs.

DISCLOSURE STATEMENT
P.M. is a nonexecutive director for the company Nevrargenics, a RAR-based drug development
company working toward understanding, treating, and potentially reversing neurodegenerative
diseases. M.U.W.-F. and A.K. are not aware of any affiliations, memberships, funding, or financial
holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
Support was received from a Biotechnology and Biological Sciences Research Council (BBSRC)
grant (BB/P004806/1) and the National Health Service (NHS) Grampian Endowments.
M.U.W.-F. is currently supported by the Intramural Research Program of the National Institutes
of Health, National Institute on Aging.

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An Accidental Nutritionist
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Omega-3 Fatty Acids and Adipose Tissue: Inflammation and Browning
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and Naima Moustaid-Moussa p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
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Roles of Regulatory RNAs in Nutritional Control
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Calorie Restriction and Aging in Humans
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Nutritional Aspects of Spermidine
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Novel Approaches for Omega-3 Fatty Acid Therapeutics: Chronic
Versus Acute Administration to Protect Heart, Brain, and Spinal
Cord
Hylde Zirpoli, Chuchun L. Chang, Yvon A. Carpentier, Adina T. Michael-Titus,
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Nutrition Regulates Innate Immunity in Health and Disease
Samuel Philip Nobs, Niv Zmora, and Eran Elinav p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Nutritional Requirements for Sustaining Health and Performance
During Exposure to Extreme Environments
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Vitamin A and Retinoic Acid in Cognition and Cognitive Disease
Marta U. Wołoszynowska-Fraser, Azita Kouchmeshky, and Peter McCaffery p p p p p p p p p p p 247
The Role of Diet in Cancer Prevention and Chemotherapy Efficacy
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Short Bowel Syndrome: A Paradigm for Intestinal Adaptation to

Nutrition?
Johanne Le Beyec, Lore Billiauws, André Bado, Francisca Joly, and Maude Le Gall p p p p 299
From Birth and Throughout Life: Fungal Microbiota in Nutrition
and Metabolic Health
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Drinking Water in the United States: Implications of Water Safety,
Access, and Consumption
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and Lorrene D. Ritchie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
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All Children Thrive: Integration of Nutrition and Early Childhood

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Policy Progress in Reducing Sodium in the American Diet, 2010–2019
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Impacts and Echoes: The Lasting Influence of the White House
Conference on Food, Nutrition, and Health
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