Glial S100A6 Degrades [beta]-amyloid Aggregation through Targeting Competition with Zinc Ions

Evidence has been accumulating that zinc ions can trigger [beta]-amyloid (A[beta]) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer's disease (AD). Chelating zinc inhibits A[beta] aggregation and may hold promise as a therapeutic strategy for AD. S100A6...

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Bibliographic Details
Published in:Aging and disease 2019-08, Vol.10 (4), p.756
Main Authors: Tian, Zhi-Ying, Wang, Chun-Yan, Wang, Tao, Li, Yan-Chun, Wang, Zhan-You
Format: Article
Language:English
Subjects:
Advertising executives
Alzheimer's disease
Genetic engineering
Protein binding
Scientific equipment industry
Toxicity
Zinc (Nutrient)
Zinc compounds
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Summary:Evidence has been accumulating that zinc ions can trigger [beta]-amyloid (A[beta]) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer's disease (AD). Chelating zinc inhibits A[beta] aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic [Ca.sup.2+]/[Zn.sup.2+]-binding protein found only in a small number of astrocytes in the normal brain. However, in the AD brain, S100A6 is highly expressed in astrocytes around A[beta] plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on A[beta] plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased A[beta] deposition and S100A6 expression, both reversible by the zinc chelator clioquinol, in the brains of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice. To examine whether exogenous S100A6 could induce A[beta] plaque disaggregation through competition for zinc in vitro, we incubated APP/PS1 mouse brain sections with recombinant human S100A6 protein or co-incubated them with human S100A6-expressing cells. Both treatments efficiently reduced the A[beta] plaque burden in situ. In addition, treatment with exogenous S100A6 protected cultured COS-7 cells against zinc toxicity. Our results show for the first time that increased S100A6 levels correlate with both A[beta] disaggregation and decrease of A[beta] plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from A[beta] deposition through zinc sequestration. Key words: S100A6, [beta]-amyloid protein, astrocyte, zinc, Alzheimer's disease
ISSN:2152-5250
2152-5250
DOI:10.14336/AD.2018.0912