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bioRxiv · 10.1101/2025.08.28.672812

Lepr Haploinsufficiency Accelerates Alzheimer-like Neurodegeneration via CDK5 Hyperactivation

Paul, S.·Bhardwaj, J.·Sharma, S.·KT, M. S.·Koul, D.·BK, B.
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Abstract

Leptin signaling has neuroprotective effects and is increasingly linked to Alzheimers disease (AD). Beyond metabolism, leptin modulates {beta}-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, A{beta}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 A{beta}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.

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Paul, S., Bhardwaj, J., Sharma, S., KT, M. S., Koul, D., BK, B.. 2025-09-02. Lepr Haploinsufficiency Accelerates Alzheimer-like Neurodegeneration via CDK5 Hyperactivation. https://doi.org/10.1101/2025.08.28.672812

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