Epidemiological studies suggest that individuals with diabetes mellitus are at greater risk of developing Alzheimer's disease. A well-known insulin-sensitizing drug and the most widely prescribed oral medication for diabetes is metformin. There is evidence that metformin acts in a neuroprotective manner via the AMPK/mTOR pathway by inhibiting the tau phosphorylation. In addition, it is known that metformin upregulates Fgf21, which in turn activates the AMPK/mTOR pathway and mediates neuroprotection. Thus, metformin-induced Fgf21 release may be involved in AMPK/mTOR activation. However, some studies reported that metformin causes cognition impairment. Due to the controversial data on the neuroprotective properties of metformin, we treated Apolipoprotein E deficient (ApoE-/-) mice, a mouse model of tauopathy, with metformin for 18 weeks. Metformin-treated mice revealed increased expression of lipogenic genes, i.e., lxr␣ and srebp1c. In line with this, metformin caused an increase in plasma triglyceride leading to enhanced gliosis as indicated by an increase of GFAP-positive cells. Although the systemic Fgf21 concentration was increased, metformin did not activate the FgfR1c/AMPK/mTOR pathway suggesting a Fgf21-resistant state. Further, metformin-treated mice showed increased tau phosphorylation and reduced numbers of NeuN-and PSD95-positive cells. Thus, metformin-associated lipogenesis as well as inflammation aggravated neurodegenerative processes in ApoE-/-mice. Consequently, this study supports previous observations showing that metformin causes impairment of cognition.
Background Strong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. A key regulator of cholesterol transport is the Apolipoprotein E4 (ApoE4), which plays a fundamental role in neuronal maintenance and repair. Impaired function of ApoE4 may contribute to altered cerebral metabolism leading to higher susceptibility to neurodegeneration. Methods To determine a possible link between ApoE function and alterations in AD in the brain of Apolipoprotein E-deficient mice (ApoE−/−) in a longitudinal manner metabolic and neurochemical parameters were analyzed. Cortical metabolism was measured by 2-deoxy-2-[18F]fluoroglucose ([18F]FDG)-PET/CT and proton magnetic resonance spectroscopy (1H-MRS) served to record neurochemical status. Results By using [18F]FDG-PET/CT, we showed that brain metabolism declined significantly stronger with age in ApoE−/− versus wild type (wt) mice. This difference was particularly evident at the age of 41 weeks in almost each analyzed brain region. In contrast, the 1H-MRS-measured N-acetylaspartate to creatine ratio, a marker of neuronal viability, did not decline with age and did not differ between ApoE−/− and wt mice. Conclusion In summary, this longitudinal in vivo study shows for the first time that ApoE−/− mice depict cerebral hypometabolism without neurochemical alterations.
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