Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner

Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5-mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3-target replacement (TR) mice, not ApoE4-TR mice. It found that in aged ApoE3-TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4-TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3-TR and ApoE4-TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype-dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4- and age-related AD prevention and treatment.-Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner.