Lepr Haploinsufficiency Accelerates Alzheimer-like Neurodegeneration via CDK5 Hyperactivation
Paul, S.; Bhardwaj, J.; Sharma, S.; KT, M. S.; Koul, D.; BK, B.
Show 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.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Canagliflozin reprograms the aging hippocampus in genetically diverse UM-HET3 mice and attenuates Alzheimer's-like pathology 97%
- Muscle Cathepsin B treatment improves behavioral and neurogenic deficits in a mouse model of Alzheimer's Disease 97%
- Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimers disease hallmarks 96%
Similar papers in this journal
- Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling 96%
- Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice 96%
- Transcriptional and translational regulation of pathogenesis in Alzheimer's disease model mice 95%
Similar papers in this journal
- Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer disease mouse model via enhancing neurotrophic and synaptic signaling 97%
- Hypothalamic Sex-Specific Metabolic Shift by Canagliflozin during Aging 96%
- Microglial MHC-I induction with aging and Alzheimer's is conserved in mouse models and humans 96%
Similar papers in this journal
- Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of Alzheimer’s disease 94%
- Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice 94%
- Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimers disease 94%
Similar papers in this journal
- Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques 97%
- Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease 95%
- APOE Genotype Influences on The Brain Metabolome of Aging Mice - Role for Mitochondrial Energetics in Mechanisms of Resilience in APOE2 Genotype. 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.