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Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc
- Source :
- Molecular Psychiatry. 25:2728-2741
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- Male
inorganic chemicals
0301 basic medicine
medicine.medical_specialty
Amyloid
Stimulation
Neuropathology
Hippocampus
Protein Aggregation, Pathological
Reuptake
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Alzheimer Disease
Risk Factors
Internal medicine
medicine
Extracellular
Animals
Senile plaques
Rats, Wistar
Molecular Biology
Amyloid beta-Peptides
business.industry
Long-term potentiation
medicine.disease
Rats
Zinc
Psychiatry and Mental health
030104 developmental biology
Endocrinology
Female
Alzheimer's disease
Extracellular Space
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14765578 and 13594184
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Molecular Psychiatry
- Accession number :
- edsair.doi.dedup.....c475530dd54be10ac8b75f05083a18e9