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

Abstract

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. FASEB J. 33, 7748–7757 (2019). http://www.fasebj.org

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status

“…The findings might explain inconsistencies in the cognitive benefits of metformin seen previously in the literature 39 . In APOE ε4 transgenic and APOE gene deficient mice, 40,41 metformin failed to activate the adenosine monophosphate kinase pathway, worsened spatial memory, and exacerbated neurodegeneration. The majority of animal or cell studies suggest that metformin can increase levels of Aβ precursor protein and β‐secretase, 42–45 or increase tau hyperphosphorylation 40,41 .…”

“…In APOE ε4 transgenic and APOE gene deficient mice, 40,41 metformin failed to activate the adenosine monophosphate kinase pathway, worsened spatial memory, and exacerbated neurodegeneration. The majority of animal or cell studies suggest that metformin can increase levels of Aβ precursor protein and β‐secretase, 42–45 or increase tau hyperphosphorylation 40,41 . We hypothesize that the interactions between metformin and the amyloid cascade in those with AD might outweigh the neuroprotective effects seen in cognitively normal people.…”

“…and β-secretase, [42][43][44][45] or increase tau hyperphosphorylation. 40,41 We hypothesize that the interactions between metformin and the amyloid cascade in those with AD might outweigh the neuroprotective effects seen in cognitively normal people. This is supported by the benefits of metformin seen in cognitive normal people particularly among those not carrying an APOE ε4 allele that accelerates AD pathology.…”

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

“…Along with neuronal loss, AD pathology is characterized by the occurrence of senile plaques, which contain Aβ depositions, neurofibrillary tangles composed of hyper-phosphorylated tau, and extensive synaptic loss [6]. The sex-based prevalence of AD is well documented, with over 60% of AD patients being female [7]. An even greater sex difference has been found in the impact of AD pathology, with each additional unit of AD pathology found to be associated with a nearly 3-fold increase in the odds of clinical AD in men compared with a more than a 22-fold increase in the odds of clinical AD in women [8].…”

“…Each ε4 allele reduces the age of AD onset by 7 to 9 years per allele copy [12,16]. Evidence indicates that the apoE4 risk for AD is greater in women than in men [7]; a single copy of the ε4 allele in women is sufficient to increase the AD disease risk associated with two copies of ε4 in men [17]. Furthermore, it has been shown that carrying the apoE ε4 allele has a larger deleterious effect on neurodegeneration, synaptic plasticity, and adult neurogenesis, and on cognitive performance in females more than males [18].…”