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Published on: June 14, 2020
Basic Science and Pathogenesis
Nicolas Gabriel Gonzalez Perez1,2, Carlos Javier Pomilio1,2, Luciano Arcucci1,2
1CONICET, Buenos Aires, Argentina.
Background:
Alzheimer's Disease (AD) and type 2 diabetes mellitus (T2D) share an exacerbated neuroinflammatory response coordinated by microglial cells and a decreased autophagic flux. Treatment with the normoglycemic metformin (MET) has been associated with reduced microglial activation and restored autophagy in T2D models. Our objective, within the framework of drug repositioning, is to evaluate the therapeutic potential of MET on experimental AD using mouse models and in vitro experiments.
Method:
We treated 9-month-old male PDAPP-J20 mice carrying AD mutations with MET (350 mg/kg i.p. three times a week for three weeks) or vehicle and we assessed cognitive profile using spatial memory tests such as the Barnes maze. From brain sections containing hippocampus, we analyzed the impact of MET on amyloid pathology, neurogenesis status by evaluation of the new-born neuron marker DCX and microglial status. In vitro, the murine BV2 microglial cell line was exposed to 0.05 µM of Aβ 1-42 for 24 hours, followed by 1 hour of treatment with 0.2 mM MET, and autophagic flux was evaluated under these conditions.
Result:
In MET-treated mice we found an improvement in spatial memory and hippocampal neurogenesis and a decrease in amyloid pathology compared to vehicle-treated group. AD mice exhibited a decrease in the homeostatic microglial marker TMEM119, which was reversed by MET treatment. Additionally, a restoration of microglial autophagic flux was observed, evidenced by a reduction in the autophagosome marker p62 in transgenic mice treated with MET. In vitro, exposure to amyloid peptides resulted in a blockade of autophagic flux, assessed by p62 accumulation using Bafilomycin, which was reversed by MET.
Conclusion:
Our results indicate that metformin may have a therapeutic effect in AD models restoring cognitive performance. This effect appears to be due to a microglial gain of function by rehabilitating the autophagic flux blocked by amyloid peptides. Metformin may also contribute to the reduction of amyloid pathology and improvement of hippocampal neurogenesis.
Insights
Metformin (MET) treatment improved cognitive function and reduced amyloid pathology in Alzheimer's Disease (AD) mouse models. This therapeutic effect is linked to restored microglial autophagic flux, suggesting MET's potential for AD treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Alzheimer's Disease (AD) and type 2 diabetes mellitus (T2D) share neuroinflammation and impaired autophagy.
- Metformin (MET), a T2D drug, reduces microglial activation and improves autophagy in T2D models.
Purpose of the Study:
- Evaluate metformin's therapeutic potential for experimental Alzheimer's Disease.
- Investigate metformin's effects on neuroinflammation, amyloid pathology, and cognitive function in AD models.
Main Methods:
- Treated PDAPP-J20 mice with metformin or vehicle, assessing spatial memory, amyloid pathology, neurogenesis (DCX), and microglial status.
- In vitro: Exposed BV2 microglial cells to amyloid-beta (Aβ) peptides and metformin, evaluating autophagic flux.
Main Results:
- Metformin improved spatial memory, hippocampal neurogenesis, and reduced amyloid pathology in AD mice.
- Metformin reversed decreased TMEM119 expression and restored microglial autophagic flux (reduced p62).
- In vitro, metformin reversed Aβ-induced autophagic flux blockade in microglial cells.
Conclusions:
- Metformin demonstrates therapeutic potential in AD models by restoring cognitive performance.
- The mechanism involves microglial functional recovery via rehabilitation of amyloid-blocked autophagic flux.
- Metformin may also reduce amyloid pathology and enhance hippocampal neurogenesis.
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