title: Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer's Disease Biology: Characterization of Putative Cognates for Therapeutic Applications.
abstract: Alzheimer's disease (AD) is a neurodegenerative process primarily characterized by amyloid-β (Aβ) agglomeration, neuroinflammation, and cognitive dysfunction. The prominent cause for dementia is the deposition of Aβ plaques and tau-neurofibrillary tangles that hamper the neuronal organization and function. Aβ pathology further affects numerous signaling cascades that disturb the neuronal homeostasis. For instance, Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ in AD.
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.
authors.forename: Niraj Kumar
authors.initials: NK
authors.lastname: Jha
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.
authors.forename: Saurabh Kumar
authors.initials: SK
authors.lastname: Jha
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.
authors.forename: Noopur
authors.initials: N
authors.lastname: Kejriwal
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.
authors.forename: Renu
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.
authors.forename: Rashmi K
authors.initials: RK
authors.lastname: Ambasta
authors.affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Shahbad Daulatpur, Delhi, India.|Department of Neurology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Pravir
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007339:Insulysin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015260:Neprilysin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D015260:Neprilysin; D007339:Insulysin
keywords: Alzheimer’s disease; Neprilysin; amyloid-β; insulin degrading enzyme; therapeutics