PINK1-AMPK Signaling is Reduced in Diabetic Human Hippocampus and Reversed by AICAR Activation of Mitophagy in an Animal Model of Tauopathy and Diabetes Induced Cognitive Impairment (DCI)

Diabetes increases the risk of cognitive impairment and Alzheimer’s disease, but the mechanisms linking metabolic stress to hippocampal neurodegeneration remain unclear. We investigated whether disruption of PINK1-AMPK signaling contributes to Diabetes Induced Cognitive Impairment (DCI) and whether activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) prevents critical metabolic, cognitive, and neuropathology processes. Hippocampal tissue from diabetic and non-diabetic human brains was analyzed for PINK1-AMPK pathway proteins and tau phosphorylation. In parallel, PINK1 wild-type and PINK1 knockout mice were fed a control diet or high-fat diet, with or without AICAR, and assessed using biochemical, mitochondrial, magnetic resonance spectroscopy, lipid, neuropathological, and behavioral measures. Diabetic human hippocampus showed reduced PINK1, phospho-AMPK, and PGC-1α levels with increased phosphorylated tau. High-fat diet feeding reproduced these changes in mice and produced greater oxidative stress, impaired mitochondrial turnover, lipid droplet accumulation, reduced neuronal metabolic markers, and increased amyloid-beta and phosphorylated tau in PINK1 knockout mice. AICAR increased AMPK phosphorylation, promoted mitochondrial mitophagy, reduced oxidative stress, and lipid accumulation. Furthermore, upregulation of AMPK by AICAR lowered amyloid-beta and phosphorylated tau levels, prevented loss of hippocampal CA1 neurons, and reduced deficits in spatial and object recognition memory. These findings show impaired PINK1-AMPK signaling is critical in biological, cognitive, and pathological processes associated with DCI. AICAR/AMPK activation is a potential therapeutic strategy for DCI.