Effect of metformin treatment on aquaporin-4 expression and amyloid-β plaque buildup in a mouse model of Alzheimer’s disease

The glymphatic system facilitates the movement of cerebrospinal fluid into the brain and the clearance of metabolic waste. Impaired glymphatic function is linked to the buildup of toxic proteins in the brain, a hallmark of many neurodegenerative diseases, including Alzheimer’s disease (AD). Aquaporin-4 (AQP4), a water channel protein, plays a key role in glymphatic clearance and dysfunctional AQP4-mediated drainage has been implicated in AD pathology. Metformin is commonly used to treat type-2 diabetes and has been shown to reduce amyloid-beta (Aβ) plaque buildup in the brains of animal models of AD, possibly through modulation of AQP4 expression. The objective of this study was to determine whether metformin modulates AQP4 expression and glymphatic function to attenuate amyloid pathology in a mouse model of AD. We hypothesized that metformin treatment enhances AQP4-mediated glymphatic clearance, thereby reducing Aβ plaque accumulation. To investigate this relationship, APP/PS1 transgenic mice and C57BL/6 mice were treated with or without metformin in their drinking water for four months. Following treatment, brain tissues were analyzed for AQP4 expression via Western blot. Fixed brain sections were also stained with Congo red to visualize Aβ plaques. Plaque volume analysis was performed using the Revolve microscope system annotate feature. Data: Preliminary data shows that brains of metformin treated mice had 44% decreased plaque load and twice the protein levels of AQP4 compared to control mice. These results suggest that metformin treatment delays plaque deposition in APP/PS1 mice at least in part due to an enhanced expression of AQP4. This supports a potential mechanism by which metformin enhances glymphatic clearance and mitigates AD pathology. This research is supported by NIH grant R25AG086106. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.