Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology
Year: 2017
Type: article
Abstract: The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.
Source: Nature Communications
Authors: Tal Nuriel, Sergio L. Angulo, Usman Khan, Archana Ashok, Qiuying Chen, Helen Y. Figueroa, Sheina Emrani, Li Liu, Mathieu Herman, Geoffrey Barrett, Valerie Savage, Luna Buitrago, Efrain Cepeda-Prado, Christine Fung, Eliana Goldberg, Steven S. Gross, S. Abid Hussaini, Herman Moreno, Scott A. Small, Karen E. Duff
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular disease and Alzheimers disease, Risk Genes and Environmental Interactions in Neural Tube Defects, Metabolite profiling to identify AD-relevant pathways affected by apoe variants, Diabetic Vasculopathy and Mitochondrial eNOS, Metabolomic/lipidomic analysis of apoE isoform effects in AD-linked brain regions, Profiling Pathologically Normal ApoE Variants to Identify Pathways for AD, Entorhinal-hippocampal circuit dysfunction in AD mice, Metabolomic/Lipidomic Analysis of ApoE Isoform Effects
OpenAlex ID: W2767500419