Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer’s Disease Gene-Dependent Mechanism in Adult Mice

Article type: Research Article

Authors: Kohler, Katharina^{a; 1} | Macheda, Teresa^{a; 1} | Hobbs, Misty M.^a | Maisel, M. Tyler^a | Rodriguez, Antonela^a | Farris, Lindsey^a | Wessel, Caitlin R.^a | Infantino, Christopher^a | Niedowicz, Dana M.^a | Helman, Alex M.^a | Beckett, Tina L.^a | Unrine, Jason M.^{b; c} | Murphy, M. Paul^{a; c; *}

Affiliations: [a] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [b] Department of Plant and Soil Sciences, University of Kentucky Martin-Gatton College of Agriculture, Food, and Environment, Lexington, KY, USA | [c] Kentucky Water Research Institute, University of Kentucky, Lexington, KY, USA | [d] Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA

Correspondence: [*] Correspondence to: M. Paul Murphy, MA, PhD, University of Kentucky, 800 South Limestone, 211 Sanders-Brown Bldg, Lexington, KY 40536-0230, USA. Tel.: 859 218 3811; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer’s disease (AD) and dementia. Objective:Although the biological mechanism underlying this link is unknown, it has been proposed that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology. Methods:We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APPΔNL/ΔNL x PS1P264L/P264L) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology. Results:Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology. Conclusions:These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.

Keywords: Aging, Alzheimer’s disease, amyloid, amyloid precursor protein, hypertension, presenilin 1, vascular contributions to cognitive impairment and dementia

DOI: 10.3233/JAD-240640

Journal: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S291-S304, 2024