Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions

Evidence has been accumulating that zinc ions can trigger β-amyloid (Aβ) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer's disease (AD). Chelating zinc inhibits Aβ aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic Ca²⁺/Zn²⁺-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 Aβ plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on Aβ plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased Aβ 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 Aβ 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 Aβ 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 Aβ disaggregation and decrease of Aβ plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from Aβ deposition through zinc sequestration.