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Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer's Disease Biology: Characterization of Putative Cognates for Therapeutic Applications

期刊

JOURNAL OF ALZHEIMERS DISEASE
卷 48, 期 4, 页码 891-917

出版社

IOS PRESS
DOI: 10.3233/JAD-150379

关键词

Alzheimer's disease; amyloid-beta; insulin degrading enzyme; Neprilysin; therapeutics

资金

  1. Delhi Technological University management

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Alzheimer's disease (AD) is a neurodegenerative process primarily characterized by amyloid-beta (A beta) agglomeration, neuroinflammation, and cognitive dysfunction. The prominent cause for dementia is the deposition of A beta plaques and tau-neurofibrillary tangles that hamper the neuronal organization and function. A beta pathology further affects numerous signaling cascades that disturb the neuronal homeostasis. For instance, A beta deposition is responsible for altered expression of insulin encoding genes that lead to insulin resistance, and thereby affecting insulin signaling pathway and glucose metabolism in the brain. As a result, the common pathology of insulin resistance between Type-2 diabetes mellitus and AD has led AD to be proposed as a form of diabetes and termed 'Type-3 diabetes'. Since accumulation of A beta is the prominent cause of neuronal toxicity in AD, its clearance is the prime requisite for therapeutic prospects. This purpose is expertly fulfilled by the potential role of A beta degrading enzymes such as insulin degrading enzyme (IDE) and Neprilysin (NEP). Therefore, their molecular study is important to uncover the proteolytic and regulatory mechanism of A beta degradation. Herein, (i) In silico sequential and structural analysis of IDE and NEP has been performed to identify the molecular entities for proteolytic degradation of A beta in the AD brain, (ii) to analyze their catalytic site to demonstrate the enzymatic action played by IDE and NEP, (iii) to identify their structural homologues that could behave as putative partners of IDE and NEP with similar catalytic action and (iv) to illustrate various IDE- and NEP-mediated therapeutic approaches and factors for clearing A beta in AD.

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