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Tytuł pozycji:

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain.

Tytuł:
Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain.
Autorzy:
Welikovitch LA; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3G 1Y6, Canada.
Do Carmo S; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada.
Maglóczky Z; Human Brain Research Laboratory, Institute of Experimental Medicine of the Hungarian Academy of Sciences, 1051 Budapest, Hungary.
Malcolm JC; Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3G 1Y6, Canada.
Lőke J; Department of Psychiatry, Szent Borbála Hospital, 2800 Tatabánya, Hungary.
Klein WL; Department of Neurobiology, Northwestern University, Evanston, IL 60208.
Freund T; Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine of the Hungarian Academy of Sciences, 1051 Budapest, Hungary.
Cuello AC; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3G 1Y6, Canada; .; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada.; Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3G 1Y6, Canada.; Department of Pharmacology, University of Oxford, OX1 2JD Oxford, Oxford, United Kingdom.
Źródło:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 24; Vol. 117 (12), pp. 6844-6854. Date of Electronic Publication: 2020 Mar 06.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:
Alzheimer Disease/*pathology
Amyloid beta-Peptides/*metabolism
Amyloid beta-Protein Precursor/*metabolism
Brain/*pathology
Inflammation/*pathology
Neurons/*immunology
Plaque, Amyloid/*pathology
Alzheimer Disease/immunology ; Alzheimer Disease/metabolism ; Amyloidosis ; Animals ; Brain/immunology ; Brain/metabolism ; Disease Models, Animal ; Female ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Male ; Neurons/metabolism ; Neurons/pathology ; Plaque, Amyloid/immunology ; Plaque, Amyloid/metabolism ; Rats ; Rats, Transgenic
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Grant Information:
PJT-364544 Canada CIHR; 2017-1.2.1-NKP-2017-00002 Canada CIHR
Contributed Indexing:
Keywords: Alzheimer’s disease; intraneuronal Aβ; neuronal inflammation; preplaque pathology
Substance Nomenclature:
0 (Amyloid beta-Peptides)
0 (Amyloid beta-Protein Precursor)
Entry Date(s):
Date Created: 20200308 Date Completed: 20200707 Latest Revision: 20200707
Update Code:
20240105
PubMed Central ID:
PMC7104377
DOI:
10.1073/pnas.1914593117
PMID:
32144141
Czasopismo naukowe
Chronic inflammation during Alzheimer's disease (AD) is most often attributed to sustained microglial activation in response to amyloid-β (Aβ) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be at play during the earliest AD-related immune response. We propose that this plaque-independent inflammatory reaction originates from neurons burdened with increasing levels of soluble and oligomeric Aβ, which are known to be the most toxic amyloid species within the brain. Laser microdissected neurons extracted from preplaque amyloid precursor protein (APP) transgenic rats were found to produce a variety of potent immune factors, both at the transcript and protein levels. Neuron-derived cytokines correlated with the extent of microglial activation and mobilization, even in the absence of extracellular plaques and cell death. Importantly, we identified an inflammatory profile unique to Aβ-burdened neurons, since neighboring glial cells did not express similar molecules. Moreover, we demonstrate within disease-vulnerable regions of the human brain that a neuron-specific inflammatory response may precede insoluble Aβ plaque and tau tangle formation. Thus, we reveal the Aβ-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of Aβ as a significant immunological component in the AD pathogenesis.
Competing Interests: The authors declare no competing interest.
(Copyright © 2020 the Author(s). Published by PNAS.)

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