Wang, Na

The prevalence of Alzheimer’s disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aβ than males, and sFRP1 protein levels were positively associated with Aβ42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.

Apolipoprotein E (APOE) is a lipid transporter involved in neural cholesterol metabolism. Highly expressed in astrocytes and microglia, APOE4, one of the three isoforms of the transporter, is a strong genetic risk factor for Alzheimer’s disease, while APOE3 is considered moderate risk and APOE2 protective. Despite recent advances in Alzheimer’s disease research, the exact mechanism by which APOE4 influences the progression of the disease has yet to be determined. One hallmark pathological feature of Alzheimer’s disease is the accumulation of hyperphosphorylated tau protein in the brain. To investigate the role of APOE isoform expression in the accumulation of hyperphosphorylated tau protein, a microglia‐specific cre‐ recombinase‐mediated APOE inducible mouse model was used. Phosphorylated‐tau accumulation, microglia activation, and neurodegeneration of the hippocampus and piriform cortex upon specific expression of APOE3 were quantified. APOE3 expressing mice had exacerbated neurodegeneration and tau accumulation in the hippocampus. Additionally, it appeared that APOE3 expressing mice had increased microglial activation. Thus, APOE expression may be involved in the activation of microglia in Alzheimer’s disease, eliciting an overactive immune response that accelerates disease progression.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.