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

Welikovitch, Lindsay A. and Carmo, Sonia do and Maglóczky, Zsófia and Malcolm, Janice C. and Lőke, János and Freund, Tamás (2020) Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 117 (12). pp. 6844-6854. ISSN 0027-8424


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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. © 2020 National Academy of Sciences. All rights reserved.

Item Type: Article
Additional Information: Cited By :11 Export Date: 7 March 2021 CODEN: PNASA Correspondence Address: Claudio Cuello, A.; Department of Neurology and Neurosurgery, Canada; email: Chemicals/CAS: amyloid beta protein, 109770-29-8; colony stimulating factor 1, 81627-83-0; macrophage inflammatory protein 1alpha, 155075-84-6; Amyloid beta-Peptides; Amyloid beta-Protein Precursor Funding details: Rotary Foundation Funding details: Canadian Institutes of Health Research, CIHR, PJT-364544 Funding details: Fonds de Recherche du Québec - Santé, FRQS Funding text 1: ACKNOWLEDGMENTS. We thank Dr. Alfredo Ribeiro-da-Silva for allowing us to use the Axio Imager M2 widefield microscope and for his guidance and assistance in acquiring the images presented; and the McGill University Advanced BioImaging Facility for their help with laser-capture microdissection and confocal microscopy. The A.C.C. laboratory is grateful for the unrestricted support received from Dr. Alan Frosst, the Frosst family, and Merck Canada. This research is supported by the Canadian Institutes of Health Research Project Grant PJT-364544 (to A.C.C.) and 2017-1.2.1-NKP-2017-00002 (to the Human Brain Research Laboratory). L.A.W. is the recipient of a Doctoral Training Fellowship from the Fonds de recherche du Québec–Santé. S.D.C. is the holder of the Charles E. Frosst/Merck Research Associate position. J.C.M. was the recipient of a Rotary Foundation Global Grant Scholarship. A.C.C. is the holder of the McGill University Charles E. Frosst/Merck Chair in Pharmacology and is a member of the Canadian Consortium on Neurodegeneration in Aging.
Uncontrolled Keywords: Aged; Female; Male; RAT; BRAIN; GENE; ARTICLE; human; priority journal; controlled study; nonhuman; animal tissue; animal experiment; animal cell; nerve cell; Gene Expression; AMYLOID PRECURSOR PROTEIN; protein expression; interleukin 6; human tissue; cell activation; Alzheimer's disease; microglia; upregulation; monocyte chemotactic protein 1; Alzheimer disease; macrophage inflammatory protein 1alpha; colony stimulating factor 1; amyloid beta protein; nervous system inflammation; tau protein; cell motility; hippocampal CA1 region; AMYLOID PROTEIN; microtubule associated protein 2; subiculum; Intraneuronal Aβ; TUBB3 gene; IL 6 gene; interleukin 12p35; CD70 antigen; Neuronal inflammation; Preplaque pathology; CCL2 gene; CCL3 gene; Cd70 gene; CSF 1 gene; IL 12a gene; MAP2 gene;
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria
Depositing User: MTMT SWORD
Date Deposited: 12 Mar 2021 14:03
Last Modified: 12 Mar 2021 14:03

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