Role of Retinoids in treatment of Alzheimer’s disease

 

Saudagar R.B., Buchake V.V. and *Bachhav R.S.

KCT’s Ravindra Gambhirrao Sapkal College of  Pharmacy. Anjaneri, Nashik-13

 

ABSTRACT:

Alzheimers disease very basically is characterized by the loss of the cognitive functions.β-amyloid is a major histopathological hallmark of Alzheimer’s disease (AD).The disease is characterized by extracellular neuritic plaque composed of fibrillar-amyloid peptide and intracellular neurofibrillary tangles containing hyperphosphorylated tau. The peptides are generated by successive proteolysis of beta amyloid precursor protein, a large transmembrane glycoprotein that is initially cleaved by the site amyloid precursor protein cleaving enzyme -1 and subsequently by gamma secretase in the transmembrane domain. Retinoic acid is active metabolite of Vitamin A. Deprivation of Vitamin A results in amyloid-β accumulation, loss of hippocampal long term potentiation and memory deficit, all of which are hall mark of Alzheimers disease. Here we focused a role of retinoic acid on different pathophysiological features of Alzheimers disease. Retinoic acid may play an active role in treating neurodegenerative disorder. Retinoids appear to normalize many pathological states, and clinical side effects presently reported are mostly not serious except for retinoic acid syndrome

 

KEYWORDS: Alzheimers, Retinoic acid, Vitamin A, amyloid-β, retinoid X receptor(RXR)

 

INTRODUCTION:

Alzheimer disease is disabling senile dementia, the loss of reasoning and ability to care for one self that afflicts about 11% of population over age of 65 and 20-25% of population over age 85.The cause of most Alzheimer disease cases is still unknown, but evidence suggest it is due to combination of genetic factors, environmental and life style factors and aging process. [1-5] The disease is characterized by extracellular neuritic plaque composed of fibrillar-amyloid peptide and intracellular neurofibrillary tangles containing hyperphosphorylated tau. The peptides are generated by successive proteolysis of beta amyloid precursor protein, a large transmembrane glycoprotein that is initially cleaved by the site amyloid precursor protein cleaving enzyme -1 and subsequently by gamma secretase in the transmembrane domain. [10]

 

Metabolite of retinoid is a retinoic acid, which has been shown to control the nuclear receptor: the retinoic acid receptors and retinoid X receptor (RXRs) [6] which then bind to retinoic acid response elements in the regulatory regions of direct target, thereby activating gene transcription. Retinoic acid receptors mediate transcription of different sets of genes of cell differentiation, thus it also depend on target cells. One of the target gene is the gene of retinoic acid receptor it self which occurs during positive regulation. [7] Deprivation of vitamin A results in amyloid beta accumulation, loss of hippocampal ling term potentiation, and memory deficits in rodents, all of which are hallmark of Alzheimer disease. [8-9]

 

Pathophysiology of Alzheimer

At an anatomical level, Alzheimers disease is characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes and synapse in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of frontal cortex and cingulated gyrus. [11]

 

Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitter serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated, [12]formation of neurofibrillary tangles, oxidation and lipid peroxidation, glutaminergic exicitotoxicity, inflammation and activation of cascade of apoptotic cell death are considered secondary consequences of the generation and deposition of beta amyloid . Cell dysfunction and cell death in nuclear groups of neurons responsible for maintenance of specific transmitter system lead to deficit in acetylcholine, norepinephrine and serotonin. Alternate hypothesis regarding   pathophysiogy of Alzheimer disease place greater emphasis on potential role of tau protein abnormalities, heavy metals, vascular factors, or viral infections. Systematic biochemical investigation   of Alzheimer disease has clearly demonstrated changes in other neurotransmitter systems such as serotonin and the noradrenaline that do not correlate strongly with the cognitive changes of Alzheimer disease. [13-15] The cause of Alzheimers disease accounts due to changes in different genes. Mutation in three different genes (coding for presenillin 1, presenillin 2 and amyloid precursor protein) leads to early onset forms of Alzheimer disease in afflilicted families but accounts for less than 1% of cases. Another gene, called Apolipoprotein E, codes for Apolipoprotein E, a protein that helps transport cholesterol in the blood. People who have one or two copies of the e4 allele of apolipoprotein E have much higher risk of developing  Alzheimer disease and an earlier age of onset  when compared with the people who have either the e2or e3 allele. [16]   Alzheimer’s disease is definitely linked to the 1st, 14th, and 21st chromosome, but other linkages are controversial and not, as yet, confirmed. While some genes predisposing to AD have been identified, such as APOE4 on chromosome19, sporadic AD also involves other risk and protective gene still awaiting confirmation. [17]

 

β-amyloid is a major histopathological hallmark of Alzheimer’s disease (AD). [18] It is associated with age related cognitive decline, neurotoxicity, and the formation of neurofibrillary tangles (NFT). [19] Therefore several β -amyloid-lowering strategies are currently developed for clinical use. These include inhibition of the generation of amyloid β peptide (A β) with β -and gamma secretase inhibitors, prevention of Amyloid β aggregation, and immunization against β -amyloid. [20] Both Passive and active immunization of transgenic mice against b amyloid can reverse neuropathology and improve pathologic learning and memory behaviours. [21]

 

Activity of retinoic acid

The biological or pharmacological activities of interest here are the important practical clinical application of retinoid in the treatment of acute promyelocytic leukemia (APL), treatment with retinoic acid results in complete remission in 90-95 % patients. [22] A synthetic retinoid, tamibarotene, works even on relapsed APL, which cannot be treated with retinoic acid. [23] Long term maintenance treatments of APL patients using retinoic acid and tamibarotene are in progress. More recently a review of retinoids for cancer and metabolic disease was published. [24] Retinoid also inhibits angiogenesis. [25] Dermatological diseases in particular psoriasis are treated with retinoic acid, etretinate, and tamibarotene. [26-27] Psoriasis is now regarded as autoimmune disease. [28]   Furthermore, retinoids is effective in the treatment of collagen –induced rheumatoid arthritis and other autoimmune models. [29-30] They are also useful to prevent atherosclerosis and restenosis of vascular vessels. [31-32] Retinoid suppress the differentiation of preadipocyte, [33] and promote alveolar regeneration in mammalian lungs. [34] Other observation suggests several clinical potential applications such as the treatment of diabetic retinopathy [35] and cataract. [36]   Animal experimentation using non-obese diabetic mice suggested that retinoids may be effective to suppress type -I diabetes and Schoegren’s syndrome, [37] Crohn’s disease is expected to be another treatment target. [38-39]

 

Retinoids appear to normalize many pathological states, and clinical side effects presently reported are mostly not serious except for retinoic acid syndrome, which seems specific to APL pathogenesis. Teratogenicity remains an issue during the organ formation period in pregnancy; absolute contraception is required until complete clearance. Genotoxicity has not been observed. Skin irritation often become a limitation in prolonged use for some retinoids, this may be caused by activation of the RAR. [40-43]

 

Approach of retinoic acid in Alzheimer disease

The major pathophysiology of Alzheimer disease is cerebral atropy and neuronal loss, neuritic plaques and neurofibrillary tangles. Age related decline of cognition which is a serious feature of Alzheimer disease could also be a target phenomenon of retinoid. [44-45]   Retinoic acid induced release of arachidonic acid is mainly released by the action of phospholipase A2 and phospholipase C/diacylglycerol lipase pathways. Abnormal retinoid metabolism may be involved in the downstream transcriptional regulation of phospholipase A2-mediated signal transduction in schizophrenia and Alzheimer disease. [46-48]

 

Neurotransmission

The features observed in Alzheimer disease are the change of cholinergic neurotransmission, which cause the decrease of acetylcholine. It was reported that vitamin A deficient rats with cognitive deficits showed impaired scopolamine evoked released of acetylcholine owing to the blockade of the presynaptic   acetylcholine autoreceptor. The impaired release of acetylcholine is probably caused by lower production of choline acetyltransferase, as well as neural cell death mediated by retinoic acid and the gene promoter. [49-50]An increase of choline acetyltransferase seems to be beneficial, and it has been suggested that the vascular acetylcholine transporter is also regulated by retinoic acid. [51] In addition, retinoid also regulate the expression of tyrosine hydroxylase, dopamine hydroxylase and the dopamine D2 receptor expression via interaction with retinoid acid response element at the promoter. [52]

 

Amyloid beta hypothesis

Dietary deficiency of vitamin A disrupts the retinoid signaling pathways in adult rats, leading to deposition of amyloid in the cerebral blood vessels via down regulation of retinoic acid receptor in the forebrain neurons and loss of choline acetyl transferase expression, and these changes were reversed by administration of retinoic acid. Pathological samples from Alzheimer disease patients showed a similar retinoic acid receptor deficit and deposition of amyloid beta in the surviving neurons. [53-54]

Amyloid precursor protein is processed and fragmented by beta secretase and gamma secretase to generate amyloid beta. However, the non amylodogenic pathway of processing precursor proteins involves cleavage within the amyloid beta peptide sequence. The identification of a member of the disintegration and metalloprotease family as an alpha secretase, whose expression can be regulated by retinoic acid, represent another therapeutic opportunity. Endogenous ADAM10 mRNA level and the ADAM10 promoter activities were increased on retinoic acid treatment in neuroblastma cells:  thus, retinoic acid works as an activator of the alpha secretase. [55-57]   

 

Neuroinflammation

Microglial cell activation and migration, participation of astrocytes, and participation of various cytolines in Alzheimer disease have been confirmed. Microglia secretes proteolytic enzymes that degrade amyloid beta, and play a neuroprotective role in Alzheimer disease. On of the chemokine receptors, CCR2 deficiency impairs microglial accumulation and accelerates the progression of Alzheimer like disease in a model mouse Tg2576. [58-59]Chronic inflammation and astrocytosis are histopathological hallmarks of Alzheimer disease patient, and astrocytes and microglia produce IL6 in response to amyloid –Beta induced injury, thereby further  promoting plaque formation . [60] The induction of IL-6 mRNA in the hippocampus and cortex of APPsw transgenic mice Tg2576 may be crucial in the elderly onset of AD. The association of 174G/C and 572 G/C mutation of IL6 promoters with Alzheimer disease has been discussed but remain contentious. [61-62]

 

T-cell differentiation

Navie CD4-positive T cells differentiate into effector T-cells (Th1, Th2, Th17) and regulatory T cells (Treg) in peripheral lymphoid tissues. Th1 cells whose differentiation is dependent on IL-12 and suppressed by retinoids mediated cellular immunity and physiological (and pathological) inflammation. Th2 cells mediate immunity and allergy. Their differentiation is dependent on IL-4 and enhanced by retinoids, but suppressed by coexistence of retinoids and TGF.IL-7 producing Th17 cells mediate pathological chronic inflammation or autoimmune inflammation. Th17 differentiation is induced by coexistence of IL-6and TGF, and maintained by IL-23.By contrast, differentiation of Treg cells is induced by TGF alone and suppressed by IL-6.Treg cells suppress effector T-cells activities and thereby maintain immune system homeostasis and self tolerance. Retinoids strongly enhance TGF –induced Treg differentiation and suppress Th-17 differntiation even in the presence of IL-6. [63]

 

Infection

Breakdown of immunity is caused by due to viral infections or other organisms. The role of infection with herpes simplex, spirochetes, and chlamydophilia in Alzheimer disease has recently been reviewed. [64-67]Various routes of infection, such as gut, nasal, skin and lung, involving viruses, bacteria, specific proteins and chemical substance have been discussed. The olfactory vector hypothesis is that xenobiotics, including viruses and toxin, immunologically pull the trigger leading neurodegeneration. [68-69]This hypothesis is supported by the finding that olfactory dysfunction is a risk factor for PD and AD. [70-71]The normal differentiation and regeneration of olfactory –related cells are also regulated by retinoic acid, and vitamin A therapy in olfactory system damage can accelerate functional recovery through RARs and retinoid X receptors (RXRs): retinoic acid supports the olfactory system throughout life. [72-73] The maintenance of olfactory function by retinoid may be preventive for the disease.

 

Regeneration of Neural cells

In many cases of regeneration and differentiation in neural injuries, retinoic acid is involved, or retinal dehydrogenase (RALDH) is produced. For example, inflammation reaction cause by spinal cord contusion in rats was followed by an increase of RALDH2 enzyme activity and local synthesis of retinoic acid. [74-76] Intracellular translocation of RAR into the nuclei of activated macrophages, surviving neurons and astrocytes near the lesion site has been reported. [77] The localization of retinoid receptors in Schwann cells correlated with inflammatory transduction pathways of IL1, IL6 and TNF. [78] Retinoic acid can induce the complete regeneration of organs that cannot normally regenerate, such as mammalian lung and retina, respecifying positional information. [79-80]   Murine F9 teratocarcinoma stem cells have been widely used as model for cellular differentiation and RA signaling during embryonic development. [81] The results suggest that retinoic acid or more generally retinoids are potential therapeutic agents for the treatment of neurodegenerative disease, promoting tissue regeneration.

 

Learning and Memory

The physiological role of retinoids in hippocampal function of adult brain has been reviewed by Lane and Bailey. [82] The enzymes that synthesized retinoic acid and RALDH protein are restricted to the meninges surrounding the hippocampus in adult brain. The presence of cellular retinol binding protein 1(CRBP1) and cellular retinoic acid binding protein 1 (CRABP) in the dendritic layers of the hippocampal formation and dentate gyrus has been demonstrated. RAR alpha and RAR gamma, rather than RAR –beta, are highly expressed in hippocampal CA1, CA2 and CA3 regions. RXRs are also express. These finding suggest that RA (and therefore retinoids) may play a central role in memory and spatial learning. Impaired long term potentiation (LTP) and long term depression (LTD) have been demonstrated in mice lacking RAR alone, or RAR and RXR. [83] Loss of synaptic plasticity in vitamin A deficient mice or aged mice. The reduction of LTD and LTP are partially reversed by RA, although precise involvement of specific genes in the regulation of synaptic plasticity has been elucidated. [84-85]

 

Transthyretin (TTR) is known to be associated with the amyloid diseases senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Transthyretin is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxin and retinol. This is how transthyretin gained its name, transport thyroxin and retinol. TTR is able to deposit as amyloid fibrils causing neurodegeneration and organ failure.TTR is thought to have beneficial side, however, in binding to the infamous beta amyloid protein, thereby preventing beta amyloid natural tendency to accumulate into the plaques associated with the early stage stage of Alzheimer disease. Preventing plaque formation is thought to enable a cell to rid itself of otherwise toxic protein form and, thus, help prevent and maybe even treat the disease. [86] The involvement of transthyretin, which was identified as a key protein by microarray analysis of genes associated with age related memory deficits. [87] TTR is a serum and cerebrospinal fluid carrier of thyroid hormone, thyroxine.TTR is also carrier of retinol from liver storage to target tissues in association with retinol binding protein. [88] TTR has been reported to be the major amyloid –beta binding protein in cerebrospinal fluid. Age related memory deficits occurred in TTR -/- mice in the water maze work task, and surprisingly, the deficits were improved by uptake of RA. It has been shown that Alzheimer disease patients have lower levels of TTR. [89] TTR and possibly a similar serum protein, insulin like growth factor –I regulates brain amyloid level. Decrease level of TTR may affect retinoid homeostasis, which is required to regulate neurogenesis and differentiation. [90-92]

 

CONCLUSION

The major pathophysiology of AD is cerebral atrophy and neuronal loss, neuritic plaques and neurofibrillary tangles. Age-related decline of cognition which is a serious feature of AD could also be a target phenomenon of a retinoid. Several evidence for the relationships between the late onset Alzheimer’s disease and retinoic acid defective signaling are depicted. Retinoic acid therapy and its metabolites preferably play vital role in management of AD and the symptoms presented at the pathophysiological level. The new retinoid analogs which easily cross the blood-brain barrier would help to lower the threats of AD symptoms and even normalize the triggering factors of AD.

 

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Received on 24.08.2011

Modified on 30.08.2011

Accepted on 08.09.2011

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Research J. Pharmacology and Pharmacodynamics. 4(3): May-June, 2012, 144-149