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

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.