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)
Year: 2026
Type: preprint
Abstract: 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.
Source: Preprints.org
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204162667