Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology.

Autor:	Nuriel T; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Angulo SL; Department of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, NY, 11203, USA., Khan U; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Ashok A; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Chen Q; Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA., Figueroa HY; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Emrani S; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Liu L; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Herman M; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Barrett G; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Savage V; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Buitrago L; Department of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, NY, 11203, USA., Cepeda-Prado E; Department of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, NY, 11203, USA., Fung C; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Goldberg E; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Gross SS; Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA., Hussaini SA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA., Moreno H; Department of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, NY, 11203, USA. Herman.Moreno@downstate.edu., Small SA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA. sas68@columbia.edu.; Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA. sas68@columbia.edu., Duff KE; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA. ked2115@columbia.edu.; Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA. ked2115@columbia.edu.; Department of Psychiatry, Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, 10032, USA. ked2115@columbia.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2017 Nov 13; Vol. 8 (1), pp. 1464. Date of Electronic Publication: 2017 Nov 13.
DOI:	10.1038/s41467-017-01444-0
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu