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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.

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Fig. 1: Age and sex affect Zn2+ release from rat acute hippocampal slices.
Fig. 2: Effects of age, sex and mitochondrial function on Zn2+ uptake in rat acute hippocampal slices.
Fig. 3: Aβ aggregation on hippocampal slices assayed by bis-ANS.
Fig. 4: Bis-ANS fluorescence of adherent Aβ1–42 predominantly on neuronal dendrites and soma of acute hippocampal slices.
Fig. 5: Bis-ANS fluorescence within acute hippocampal slices treated with Aβ1–42.
Fig. 6: Effects of Zn2+-Aβ complexes on acute hippocampal slice electrophysiology and viability.
Fig. 7: Model for synaptic Zn2+ release in the pathogenesis of AD.

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Funding

This project was funded by grants from The National Health and Medical Research Council (GNT1103703, GNT1101533). The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.

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ZD and AIB designed the experimental approach, analyzed and interpreted the data, generated the figures, funded the studies, and wrote the manuscript. ZD performed the major experiments, with experimental contributions from the other authors. All authors edited the manuscript.

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Correspondence to Zsolt Datki or Ashley I. Bush.

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AIB is a shareholder in Alterity Ltd, Cogstate Ltd, Brighton Biotech LLC, Grunbiotics Pty Ltd, Eucalyptus Pty Ltd, and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in Collaborative Medicinal Development Pty Ltd.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (The University of Szeged; approval number: I-02442/001/2006).

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Datki, Z., Galik-Olah, Z., Janosi-Mozes, E. et al. Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc. Mol Psychiatry 25, 2728–2741 (2020). https://doi.org/10.1038/s41380-020-0800-y

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