Title: Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target.

Authors: Syeda, Tauqeerunnisa; Cannon, Jason R

Published In J Biochem Mol Toxicol, (2021 Apr)

Abstract: Alzheimer's disease (AD) is a major public health crisis due to devastating cognitive symptoms, a lack of curative treatments, and increasing prevalence. Most cases are sporadic (>95% of cases) after the age of 65 years, implicating an important role of environmental factors in disease pathogenesis. Environmental neurotoxicants have been implicated in neurodegenerative disorders including Parkinson's Disease and AD. Animal models of AD and in vitro studies have shed light on potential neuropathological mechanisms, yet the biochemical and molecular underpinnings of AD-relevant environmental neurotoxicity remain poorly understood. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potentially critical pathogenic target of environmentally induced neurotoxicity. BACE1 clearly has a critical role in AD pathophysiology: It is required for amyloid beta production and expression and activity of BACE1 are increased in the AD brain. Though the literature on BACE1 in response to environmental insults is limited, current studies, along with extensive AD neurobiology literature suggest that BACE1 deserves attention as an important neurotoxic target. Here, we critically review research on environmental neurotoxicants such as metals, pesticides, herbicides, fungicides, polyfluoroalkyl substances, heterocyclic aromatic amines, advanced glycation end products, and acrolein that modulate BACE1 and potential mechanisms of action. Though more research is needed to clearly understand whether BACE1 is a critical mediator of AD-relevant neurotoxicity, available reports provide convincing evidence that BACE1 is altered by environmental risk factors associated with AD pathology, implying that BACE1 inhibition and its use as a biomarker should be considered in AD management and research.

PubMed ID: 33393683

MeSH Terms: Aged; Alzheimer Disease*/enzymology; Alzheimer Disease*/etiology; Alzheimer Disease*/pathology; Amyloid Precursor Protein Secretases/biosynthesis*; Animals; Aspartic Acid Endopeptidases/biosynthesis*; Brain/enzymology*; Brain/pathology; Disease Models, Animal; Environmental Exposure/adverse effects*; Female; Gene Expression Regulation, Enzymologic*; Humans; Male; Neurotoxicity Syndromes*/enzymology; Neurotoxicity Syndromes*/etiology; Neurotoxicity Syndromes*/pathology; Neurotoxins/toxicity*