Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc.

Molecular Psychiatry
Zsolt DatkiAshley I Bush

Abstract

Aging and female sex are the major risk factors for Alzheimer's disease and its associated brain amyloid-β (Aβ) neuropathology, but the mechanisms mediating these risk factors remain uncertain. Evidence indicates that Aβ aggregation by Zn2+ released from glutamatergic neurons contributes to amyloid neuropathology, so we tested whether aging and sex adversely influences this neurophysiology. Using acute hippocampal slices, we found that extracellular Zn2+-elevation induced by high K+ stimulation was significantly greater with older (65 weeks vs 10 weeks old) rats, and was exaggerated in females. This was driven by slower reuptake of extracellular Zn2+, which could be recapitulated by mitochondrial intoxication. Zn2+:Aβ aggregates were toxic to the slices, but Aβ alone was not. Accordingly, high K+ caused synthetic human Aβ added to the slices to form soluble oligomers as detected by bis-ANS, attaching to neurons and inducing toxicity, with older slices being more vulnerable. Age-dependent energy failure impairing Zn2+ reuptake, and a higher maximal capacity for Zn2+ release by females, could contribute to age and sex being major risk factors for Alzheimer's disease.

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Citations

Nov 22, 2020·The Journal of Biological Chemistry·Peng LeiAshley I Bush
Mar 23, 2021·Frontiers in Molecular Neuroscience·Nicholas Peoples, Candace Strang

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Methods Mentioned

BETA
Fluorescence
chip
fluorescence microscopy
transgenic

Software Mentioned

ExVis
HATU
HOAt
DIEA

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