Modulation of Amyloid and Tau Pathology by Empagliflozin in a High‐Fat Diet and Streptozotocin‐Induced Type 2 Diabetes‐Associated Alzheimer's Model

Type 2 diabetes mellitus (T2DM) contributes notably to the development and progression of Alzheimer's disease (AD) through overlapping pathological mechanisms such as insulin resistance, amyloid-β (Aβ) accumulation and tau hyperphosphorylation. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently emerged as promising candidates for neuroprotection in metabolic disorders. The present work explored the potential therapeutic impact of the SGLT2 inhibitor empagliflozin (EMPA) compared with the acetylcholinesterase inhibitor rivastigmine (RIV) in a T2DM-induced AD rat model. The T2DM-AD model was established using a high-fat diet in combination with subsequent low-dose streptozotocin (35 mg/kg) administration. Metabolic, behavioural, biochemical, molecular and histopathological parameters were assessed to evaluate disease progression and treatment efficacy. EMPA significantly improved glucose metabolism, lowered nonfasting blood glucose, enhanced oral glucose tolerance and restored insulin levels in peripheral and central tissues. EMPA ameliorated short-term and spatial memory deficits and reduced Aβ and phosphorylated tau levels in the brain, serum and pancreas and normalized acetylcholinesterase and glycogen kinase-3β expression. Histological and immunohistochemical analyses corroborated these neuroprotective effects, revealing reduced neurodegeneration and proteinopathy in the cerebral cortex and hippocampus. EMPA exerts multifaceted neuroprotective and metabolic benefits in a T2DM-induced AD model, offering a therapeutic advantage over RIV by targeting both peripheral metabolic dysfunction and central neurodegeneration. By demonstrating that modulation of systemic glucose homeostasis can directly influence amyloid and tau pathology as well as cognitive outcomes, these findings provide important insight into the metabolic-neurodegenerative interface and highlight SGLT2 inhibition as a promising strategy for diabetes-associated cognitive decline and AD within the field of neuroscience.