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Tytuł:
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APP Family Regulates Neuronal Excitability and Synaptic Plasticity but Not Neuronal Survival.
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Autorzy:
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Lee SH; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Kang J; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ho A; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Watanabe H; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bolshakov VY; Department of Psychiatry, McLean Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Shen J; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: .
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Źródło:
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Neuron [Neuron] 2020 Nov 25; Vol. 108 (4), pp. 676-690.e8. Date of Electronic Publication: 2020 Sep 04.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [Cambridge, Mass. : Cell Press, c1988-
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MeSH Terms:
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Aging/*physiology
Amyloid beta-Protein Precursor/*physiology
Cerebral Cortex/*physiology
Hippocampus/*physiology
Neuronal Plasticity/*physiology
Neurons/*physiology
Animals ; Anthracenes/pharmacology ; Apoptosis/physiology ; Behavior, Animal/physiology ; Cell Survival ; Excitatory Postsynaptic Potentials/physiology ; KCNQ1 Potassium Channel/antagonists & inhibitors ; Mice ; Mice, Knockout
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Grant Information:
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R01 NS041783 United States NS NINDS NIH HHS; R01 NS042818 United States NS NINDS NIH HHS; RF1 AG063520 United States AG NIA NIH HHS
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Contributed Indexing:
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Keywords: APLP1; APLP2; LTP; M-channel; Presenilin; apoptosis; cerebral cortex; conditional knockout; hippocampus; knockout
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Substance Nomenclature:
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0 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone)
0 (Amyloid beta-Protein Precursor)
0 (Anthracenes)
0 (KCNQ1 Potassium Channel)
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Entry Date(s):
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Date Created: 20200906 Date Completed: 20210122 Latest Revision: 20231017
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Update Code:
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20240104
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PubMed Central ID:
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PMC7704911
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DOI:
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10.1016/j.neuron.2020.08.011
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PMID:
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32891188
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Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer's disease. Despite its importance, the role of APP family in neuronal function and survival remains unclear because of perinatal lethality exhibited by knockout mice lacking all three APP family members. Here we report that selective inactivation of APP family members in excitatory neurons of the postnatal forebrain results in neither cortical neurodegeneration nor increases in apoptosis and gliosis up to ∼2 years of age. However, hippocampal synaptic plasticity, learning, and memory are impaired in these mutant mice. Furthermore, hippocampal neurons lacking APP family exhibit hyperexcitability, as evidenced by increased neuronal spiking in response to depolarizing current injections, whereas blockade of Kv7 channels mimics and largely occludes the effects of APP family inactivation. These findings demonstrate that APP family is not required for neuronal survival and suggest that APP family may regulate neuronal excitability through Kv7 channels.
Competing Interests: Declaration of Interests J.S. is a member of the Board of Directors and has a financial interest in iNeuro Therapeutics J.S. also has a financial interest in Apres Therapeutics. Both companies develop therapies for AD. J.S.’s interests were reviewed and are managed by Brigham and Women’s Hospital (BWH) and Partners HealthCare in accordance with their conflict-of-interest policies.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Comment in: Neuron. 2020 Nov 25;108(4):583-585. (PMID: 33242425)
