Localized APP expression results in progressive network dysfunction by disorganizing spike timing.

Autor:	Viana da Silva S; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; NeuroCure Excellence Cluster and German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany., Haberl MG; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Neuroscience Research Center, Charitéplatz 1, 10117 Berlin, Germany., Gaur K; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA., Patel R; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA., Narayan G; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA., Ledakis M; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA., Fu ML; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA., de Castro Vieira M; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Neuroscience Research Center, Charitéplatz 1, 10117 Berlin, Germany., Koo EH; Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA., Leutgeb JK; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. Electronic address: jleutgeb@ucsd.edu., Leutgeb S; Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA, USA. Electronic address: sleutgeb@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Jan 03; Vol. 112 (1), pp. 124-140.e6. Date of Electronic Publication: 2023 Oct 30.
DOI:	10.1016/j.neuron.2023.10.001
Abstrakt:	Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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