Lepr Haploinsufficiency Accelerates Alzheimer-like Neurodegeneration via CDK5 Hyperactivation

Leptin signaling has neuroprotective effects and is increasingly linked to Alzheimer's disease (AD). Beyond metabolism, leptin modulates β-amyloid metabolism, tau phosphorylation, and synaptic plasticity. While homozygous Lepr mutations are well studied, the impact of heterozygous mutations on neurodegeneration is unclear. To assess partial Lepr loss, one-year-old db/+ mice were evaluated for metabolic, behavioral, and neuropathological changes. Tests included glucose tolerance, memory assays, Aβ 42 and tau levels, CDK5 activity, and transcriptomics. Human LEPR variants were curated and classified using ACMG guidelines. Aged db/+ mice showed metabolic dysfunction, cognitive deficits, and AD-like pathology. Compared to controls, db/+ mice had increased body weight, insulin resistance, memory impairments, elevated Aβ 42 , tau hyperphosphorylation, CDK5 hyperactivation, and astrocyte activation. Transcriptomics revealed altered synaptic and mitochondrial pathways. Thirty-three pathogenic or likely pathogenic human LEPR variants were identified. Lepr haploinsufficiency contributes to age-related cognitive decline and AD-like pathology, suggesting it as a genetic risk factor and therapeutic target.