ApoE4 Upregulates GSK‐3β to Aggravate Alzheimer‐Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice

ABSTRACT Background The apolipoprotein E (ApoE) ε4 allele and type 2 diabetes mellitus (T2DM) are independent risk factors for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder in the elderly. The T2DM patients carrying the ApoE ε4 allele exhibit heightened activation of platelet glycogen synthase kinase‐3β (GSK‐3β), a key downstream kinase in the insulin signaling pathway, along with more severe cognitive deficits. This observation suggests an intrinsic link between ApoE ε4, GSK‐3β, and cognitive dysfunction. However, the precise mechanisms by which ApoE ε4 influences GSK‐3β activity and exacerbates brain pathology and cognitive decline in T2DM patients remain poorly understood. Methods To investigate these mechanisms, we developed T2DM mouse models by generating humanized ApoE ε3/ε3 and ε4/ε4 knock‐in mice. The mice were subjected to a high‐fat diet combined with multiple low‐dose intraperitoneal streptozotocin injections to induce T2DM. We then assessed GSK‐3β expression, AD‐like pathologies, and cognitive functions in these models. Results We observed that GSK‐3β activity was significantly upregulated in ApoE4 mice, accompanied by disruption of the insulin signaling pathway. Notably, ApoE4‐T2DM mice exhibited exacerbated AD‐related pathologies, including increased accumulation of hyperphosphorylated tau, neuroinflammation, and synaptic loss. These changes were correlated with more severe cognitive impairments compared with ApoE3‐T2DM or ApoE4 mice. Furthermore, inhibition of GSK‐3β activity using the selective inhibitor 9‐ING‐41 effectively ameliorated both AD‐like pathologies and cognitive deficits in ApoE4‐T2DM mice. Conclusions Our findings suggest that ApoE4 exacerbates AD pathogenesis by activating GSK‐3β. Furthermore, targeting GSK‐3β may offer a promising therapeutic strategy to halt the progression from T2DM to AD, providing new insights into potential interventions for patients at risk.