Vitamin A as a Potential Therapy to Prevent Alzheimer’s Disease

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Vitamin A as a Potential Therapy to Prevent Alzheimer’s Disease

Abstract:

Alzheimer’s disease has a many different biological markers including oxidative stress, amyloid β plaque buildup, and inflammation. Dietary supplementation of retinoids may play a role in preventing the neurodegenerative disorder. Studies have shown retinoids help to decrease amyloid β. Buildup of Amyloid β prevents the synthesis of retinoic acid in the brain. When there are inflammatory cytokines the clearing of amyloid β by microglia in the brain is decreased because the cytokines inactivate the microglia phagocytosis. Mice that had oxidative stress in the brain and were given all-trans retinoic acid had significant improvement in memory deficits.

Introduction:

Alzheimer’s disease is the leading neurodegenerative disease in elderly adults. It affects more than 30 million people in the world (1). There are a few major markers behind Alzheimer’s disease. These include amyloid β plaque, oxidative stress, and inflammation. A potential target for the treatment of Alzheimer’s disease are the processes involved in the synthesis, transport, and function of retinoids.

Retinoids are vitamin A derivatives. They help to regulate differentiation and cell proliferation. Higher expression of retinoid signaling takes place in neuronal plasticity areas such as the hippocampus, retrosplenial, and prefrontal cortex (2). Retinoid signaling in the brain helps to control the brain functions. These include neurotransmitter release, neuronal differentiation, neurite growth, and long term potentiation (3). Retinoids are mediated by nuclear receptors (4). These nuclear receptors include retinoic acid receptors α, β, γ, and retinoid x receptors α, β, and γ.

Retinoids affect many different pathways. Some of the same pathways that retinoids affect are also affected when a person has Alzheimer’s disease. Retinoids regulate the expression receptors, neurotransmitter transporters, cell surface receptors, gene encoding enzymes, transcription factors, and neuropeptide hormones (3). A decrease in retinoic acid signaling may be associated with Alzheimer’s disease because it affects many different pathophysiological pathways (5). These pathways include amyloid β, neurotransmission, inflammation, and neurogenesis (3). Retinoids also regulate a few of the genes for neurons that contain recognition sequences for the retinoid receptor proteins.

One marker of Alzheimer’s disease are amyloid plaques. These plaques are extracellular deposits of protein in the brain. KDa amyloid β peptide (amyloid β) form the plaque. Amyloid β is a peptide chain consisting of 38-42 amino acids (1). Small amyloid β oligomers can cause neurotoxic this can cause different pathophysiological events to occur. This includes inflammation, synaptic dysfunction, inhibition of hippocampal long-term potentiation, loss of neurons, and neurofibrillary tangles. These pathophysiological events can lead to the onset of Alzheimer’s disease and eventually death.

Another marker of Alzheimer’s disease is inflammation within the brain. When there is inflammation in the brain there is proliferation of microglia and increased expression of cytokines.

In Alzheimer’s disease another pathogenesis is oxidative stress and an increase in the formation of free radicals. Retinoic acid nuclear receptors can prevent oxidative stress by regulating gene expression. Retinoic acid also helps to protect neurons by decreasing the mitochondrial oxidative damage. Retinoic acid stimulates phospholipase A2 which makes arachidonic acid metabolites. The metabolites control neurite outgrowth, long-term potentiation and neurotransmitter release (4). When too much arachidonic acid metabolites are produced there is inflammation, oxidative stress, and neurodegeneration.

The purpose of this paper is to examine if vitamin A supplementation can be used in the treatment of Alzheimer’s disease. There have been numerous studies examining the effect retinoids have on the brain. Retinoids decrease oxidative stress, inflammation and amyloid β plaque buildup in extracellular tissue. These are all markers found in patients with Alzheimer’s disease.

Amyloid β:

In order to form amyloid β there needs to be β- and γ-secretases (which are membrane proteins) to cleave the amyloid precursor protein. Β-secretase cleaves amyloid precursor protein at the N-terminal of the amyloid β (6). Amyloid β can prevent the synthesis of retinoic acid in the brain as well as microglia. The effects of amyloid β on the synthesis of retinoic acid in the brain can be reversed with a decrease in the accumulation of amyloid β in extracellular plaques and retinoic acid receptor α (3).

Amyloid β clearance, not the excessive production of amyloid β, is one possible cause of Alzheimer’s disease (3). Research has shown the agonist of retinoic acid receptor α is effective in lowering amyloid β levels. This is because there is an increase in the activity of alpha secretase which causes an increase in the non-amyloidogenic processing of amyloid precursor protein compared to amyloidogenic cleavage.

Mice that are treated for six weeks with amyloid plaque show a 60% increase in their plaque load (3). While mice treated with the retinoic acid receptor α agonist had a decrease of amyloid plaque by 50%. This demonstrates the effect of retinoic acid receptor α agonist is not only to reduce production of amyloid β it also helps to facilitate the clearance of plaque. The retinoic acid receptor β agonist and the retinoic acid receptor γ agonist did not have any effect on the plaque. This means that the reduction of amyloid β levels is mediated by retinoic acid α.

The microglial cells in the brain help to clear amyloid β plaque. In retinoic acid receptors β antibodies were expressed in amyloid plaque. There was a significant decrease in retinoic acid synthesis in the mice treated with only amyloid plaque, which was reversed by the retinoic acid receptor α agonist. The amyloid β also caused a significant decrease in the amyloid β insulin degrading enzyme (IDE) activity. IDE is a mechanism in which microglia promote proteloytic amyloid β clearance. An increase in amyloid β causes an increase in apoE (3). The IDE activity is facilitated by apoE. The retinoic acid receptor α agonist reversed the amyloid β- induced suppression of IDE activity.

When cytokines were released it caused a down regulation of genes that take part in the clearance of the amyloid β. These genes include IDE and NEP (3). Retinoic acid receptor α agonist caused amyloid β treated microglial cultures to significantly decrease the TNFα that was released. The retinoic acid receptor α agonist also significantly decreased the levels of amyloid β in the cultures compared with control cultures.

There may be a local increase in soluble oligomer due to the decrease of amyloid β plaque. There is an association between increased concentration of neurotoxic amyloid β dimers and plaque (3). The neurons cultured with oligomer and retinoic acid receptor α agonist had significantly fewer oligomers around the neuron surface than the neurons cultured with only the oligomers. The neurons with retinoic acid receptor α agonist were immunostained for neprilysin (NEP) and IDE and showed a significant increase in both the NEP and IDE enzyme activities. NEP and IDE are the mechanisms by which microglia promote amyloid β clearance. NEP is a mechanism for cleaving amyloid β. This cleaving causes a reversal of the amyloid β suppression (3). This demonstrates what when retinoic acid receptor α agonist are present there is an increase in NEP and IDE which increases amyloid β clearance.

Another sign of Alzheimer’s disease is the intracellular build-up and hyper phosphorylation of tau into neurofibrial tangles. Tau phosphorylation inhibition is important in Alzheimer’s disease therapy. Dimers of amyloid β cause the phosphorylation of tau. Tau is then freed from the microtubule network by intracellular oligomers. The freeing of Tau leads to impaired intracellular transport (3).

When mice were given retinoic acid receptor α agonist the phosphorylation of tau at AT8 and s396 was decreased. There was also an increase in phosphorylated GSK3beta which caused an increase in the clearance of amyloid β (3).

The signaling pathway for retinoic acid can be linked to amyloid β. When the pathway is disturbed by amyloid β it can be restored to normal levels by retinoic acid receptor α agonist. This would allow the brain to decrease the production and increase the clearance of excessive amyloid β.

Retinoic acid receptor α is the predominant retinoic acid receptor expressed in the central nervous system. This receptor plays a role in the maintenance of the brain homeostasis.

Vitamin A deficiency causes a decrease in retinoid signaling which causes an accumulation of amyloid β in the brain (5).

Inflammation:

Increased inflammation is associated with Alzheimer’s disease. Microglia clears amyloid β by phagocytosis and aggregates. This clearing is decreased when there are inflammatory cytokines (7). This is because the cytokines inactivate the microglia phagocytical. When the amyloid β signaling pathway is activated there is a release of proinflammatory cytokines which promote more plaque formation.

Retinoids enhance the expression of neurotrophic factor (BDNF) which have neuroprotective abilities. The neurons exposed to amyloid β by retinoid acid cause inflammatory cell death (9). The retinoids also suppress the amyloid β formation in microglia. In addition retinoids may inhibit the production of IL6 from microglia (5). Retinoids can be used to suppress inflammation and increase amyloid phagocytosis.

Amyloid β can decrease the synthesis of retinoic acid. The decrease in retinoic acid synthesis is associated with loss of activity of NEP and IDE as well as an increase in the secretion of phosphorylation of tau and inflammatory cytokine TNFα. These can be reversed by a reduction of amyloid β in extracellular plaques and retinoic acid receptor α agonist (3).

Oxidative stress:

All-trans retinoic acid is a lipophilic, bioavailable active isoform of retinoic acid. Mice given steptozotocin to model Alzheimer’s disease displayed abnormal biochemical alterations and cognitive deficits in their brain (2). Steptozotocin produces oxidative stress and impairment of brain energy metabolism. Mice that were given steptozotocin and then an administration of all-trans retinoic acid showed significant improvement in memory deficits (2).

The administration of all-trans retinoic acid significantly improved memory deficits caused by steptozotocin induced dementia (2). The administration of all-trans retinoic acid did not reverse all of the damage that steptozotocin caused. When mice were given steptozotocin the brain reduced glutathione levels and the brain thiobarituric acid reaction levels were accentuated. This means the oxidative stress levels in the brain decreased when given all-trans retinoic acid.

People and mice with Alzheimer’s disease have elevated oxidative stress levels. Giving them all-trans retinoic acid is a possible way to decrease the oxidative stress levels in the brain.

Conclusion:

Retinoids can be used as a therapy to prevent Alzheimer’s disease. Vitamin A has an effect on many of the metabolic markers of Alzheimer’s disease. These include inflammation, oxidative stress, and amyloid β in the extracellular. Targeting the receptors for these processes may slow down or reverse Alzheimer’s disease.

The research into the effect Vitamin A has on Alzheimer’s disease needs to be furthered. One avenue to further it would be examining retinoic acids in vivo. This would allow the retinoid mechanisms of action and their receptors in Alzheimer’s disease to be better understood. Another method to further research would be to study the affect retinoic acid has on amyloid β in Alzheimer’s disease using different techniques, such as histopathological observation.

References:

  1. Lichtenthaler SF. Alpha-secretase in Alzheimer’s disease: molecular identity, regulation and therapeutic potential. Journal of Neurochemistry. 2011;116:10-21.
  2. Sodhi RK, Singh N. All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of steptozotocin-induced dementia of Alzheimer’s type. Progress in Neuro-Psychopharmacology & Biological Psychiatry . 2013;40:38-46.
  3. Goncalves MB, Clarke E, Hobbs C, Malmqvist T, Deason R, Jack J, Corcoran J. Amyloid b inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor a agonist. European Journal of Neuroscience. 2013;37:1182-1192.
  4. Lee HP, Casadesus G, Zhu X, Lee H, Perry G, Smith MA, Gustaw-Rothenberg K, Lerner A. All-trans-retinoic acid as a novel therapeutic strategy for Alzheimer's disease. Expert Review of Neurotherapeutics. 2009;9:1615–1621.
  5. Sodhi R, Singh N. Retinoids as potential targets for Alzheimer’s disease. Pharmacolo Biochem Behav. 2014;
  6. Macias MM, Gonzales AM, Siniard AL, Walker AW, Corneveaux JJ, Huentelman MJ, Sabbagh MN, Decourt B. A cellular model of amyloid β precursor protein processing and amyloid-β peptide production. Journal of Neuroscience Methods. 2014;223:114-122.
  7. Culpan D, Kehoe P, Love S. Tumorn necrosis factor-α and miRNA expression frontal and temporal neocortex in Alzheimer’s disease and the effect of TNF-α on miRNA expression in vitro. Int J Mol EpidemiolGenet. 2011;2:156-162.
  8. Gropper S, Smith J. Advanced Nutrition and Human Metabolism. 6th ed. Wadesworth, CA: CengageLearning; 2013:371-389.
  9. Shudo K, Fukasawa H, Nakagomi M, Yamagat N. Towards retinoid therapy for Alzheimer’s disease. Current Alzheimer’s Research. 2009;6:302-311.

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