Effect of metformin on anti-Alzheimer activity of rivastigmine in aluminum chloride-induced Alzheimer's disease in rats: A behavioral, biochemical, immunohistopathological evidence of crosstalk between amyloid, tau, autophagy, and apoptosis.

AIM: This study investigates how the anti-Alzheimer's effectiveness of rivastigmine (RIVA) is affected by the antidiabetic drug metformin (MET).

METHODOLOGY: Male rats were randomly divided into a control group, an Alzheimer's disease (AD) group receiving aluminum chloride (AlCl3), a RIVA-treated group, a MET-treated group, and a RIVA + MET combination group. Cognitive performance was assessed using passive avoidance (PA), the radial arm maze (RAM), the Morris water maze (MWM), and novel object recognition (NOR) tests. Hippocampal microtubule-associated protein tau (MAPT), beta-site APP cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), and autophagy marker Sequestosome 1 (SQSTM1/p62) were measured, while amyloid-beta (Aβ) and caspase-3 expression were analyzed immunohistochemically. Histopathology and electron microscopy were used to assess neuronal integrity.

RESULTS

MET, RIVA, and their combined treatment mitigated the neurodegenerative alterations induced by AlCl3. The combination of MET + RIVA failed to yield significant differences in behavioral performance [PA, RAM, MWM, and NORT], MAPT levels, and AChE activity compared with the treatment with RIVA monotherapy. However, the combination therapy showed significant reductions in hippocampal BACE1, Aβ deposition, and SQSTM1/p62 levels, indicating enhanced suppression of amyloidogenic processing and improved autophagy. Although differences between MET + RIVA combination and RIVA monotherapy were not statistically significant for these markers, the combination markedly reduced caspase-3 immunoreactivity compared with the diseased group, indicating greater attenuation of apoptosis.

CONCLUSION

These results highlight the crosstalk among the amyloid, tau, autophagy, and apoptotic pathways in AD and suggest that the MET + RIVA combination showed promising molecular improvements but no clear behavioral superiority, indicating the need for further optimization.