| Autor: |
Datki Z; Department of Psychiatry, University of Szeged, Szeged, 6725, Hungary. datki.zsolt@med.u-szeged.hu., Galik-Olah Z; Department of Psychiatry, University of Szeged, Szeged, 6725, Hungary., Janosi-Mozes E; Department of Psychiatry, University of Szeged, Szeged, 6725, Hungary., Szegedi V; Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, 6726, Hungary., Kalman J; Department of Psychiatry, University of Szeged, Szeged, 6725, Hungary., Hunya ÁG; Department of Medical Chemistry, University of Szeged, Szeged, 6726, Hungary., Fulop L; Department of Medical Chemistry, University of Szeged, Szeged, 6726, Hungary., Tamano H; Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan., Takeda A; Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan., Adlard PA; Melbourne Dementia Research Centre, Florey Institute of Neuroscience & Mental Health, and The University of Melbourne, Parkville, VIC, 3052, Australia., Bush AI; Melbourne Dementia Research Centre, Florey Institute of Neuroscience & Mental Health, and The University of Melbourne, Parkville, VIC, 3052, Australia. ashley.bush@florey.edu.au. |
| Abstrakt: |
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 Zn 2+ 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 Zn 2+ -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 Zn 2+ , which could be recapitulated by mitochondrial intoxication. Zn 2+ :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 Zn 2+ reuptake, and a higher maximal capacity for Zn 2+ release by females, could contribute to age and sex being major risk factors for Alzheimer's disease. |
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