https://onlinelibrary.wiley.com/doi/10.1111/acel.70101
A recent study published in Aging Cell explores this possibility using Enavogliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. The study examines whether this anti-diabetic medication might influence Alzheimer’s pathology by targeting glucose handling, inflammation, and mitochondrial function within the brain.
Using a well-established Alzheimer’s mouse model, researchers found that Enavogliflozin treatment led to improvements in cognitive function, reduced amyloid-beta (Aβ) pathology, and altered immune signaling in the brain. While further studies are needed to evaluate its relevance in humans, these findings raise important questions about the potential for repurposing metabolic drugs in the context of neurodegeneration.
Study Overview and Key Findings
The study used 5XFAD mice, which carry multiple mutations associated with familial Alzheimer’s disease and rapidly develop Aβ plaques and cognitive deficits. Mice were treated daily with Enavogliflozin for eight weeks, beginning at five months of age—an early symptomatic phase in this model.
At the higher dose (1 mg/kg), Enavogliflozin significantly improved performance in spatial learning and memory tasks, including the Morris Water Maze and Y-maze. These behavioral improvements were accompanied by:
- Increased expression of brain-derived neurotrophic factor (BDNF),
- Restoration of postsynaptic density protein 95 (PSD95),
- Elevated acetylcholine levels—suggesting enhanced cholinergic tone.
On the pathological side, Aβ42 and Aβ40 levels were reduced, and the size and number of dense-core plaques declined—particularly larger plaques (>60 μm²). These effects occurred without changes in amyloid precursor protein (APP) expression, pointing instead to enhanced Aβ clearance.
Mechanistic Insight: Mitochondrial Modulation and Microglial Function
One of the study’s more mechanistically interesting findings centers on microglial energy metabolism. Microglia are key immune cells in the brain that help clear Aβ via phagocytosis—a process that is energetically demanding.
The researchers found that Enavogliflozin enhanced microglial phagocytic capacity through activation of AMPK (AMP-activated protein kinase), a central energy sensor known to promote mitochondrial biogenesis and efficiency. This was supported by multiple lines of evidence:
- Increased AMPK phosphorylation in both in vitro and ex vivo microglia,
- Elevated mitochondrial mass (Mitotracker staining),
- Improved oxygen consumption and ATP production (Seahorse assay),
- Reduced mitochondrial oxidative stress (MitoSOX fluorescence).
Notably, these mitochondrial and immunometabolic changes were observed without alterations in SGLT2 expression, implying that the effects were mediated via pharmacologic inhibition rather than changes in transcription.
Neuroinflammation and Immune Modulation
The study also documented a reduction in neuroinflammatory markers. Enavogliflozin treatment decreased levels of phosphorylated NF-κB, TNFα, and IL-1β in the brain, and reduced microgliosis and astrogliosis.
Interestingly, microglial—but not astrocytic—activation correlated strongly with Aβ plaque burden, suggesting that microglia may play a more direct role in the drug’s observed effects on plaque pathology. Increased clustering of Iba1-positive microglia around plaques, along with enhanced phagocytosis, supports this interpretation.
Caveats
While the findings are promising, several caveats must be considered:
- Translational Relevance: These results were observed in a specific transgenic mouse model that does not exhibit significant tau pathology, a major feature of human Alzheimer’s disease.
- BBB Penetrance: Although Enavogliflozin has low brain penetrance in healthy mice, the authors report greater brain exposure in the 5XFAD model—likely due to compromised blood-brain barrier integrity. Whether this reflects human AD pathology remains uncertain.
- Mechanistic Complexity: The relative contributions of central versus peripheral effects (e.g., systemic glucose control vs. direct CNS action) remain unresolved. Further studies with CNS-specific delivery or genetic models would help disentangle these mechanisms.