Abstract
Neuroinflammation is involved in the pathogenesis of Alzheimer's disease, and the transcription factor NF-κB is a player in this event. We found here that the ischemic damage alone or in association with Aβ1-42 activates the NF-κB pathway, induces an increase of BACE1 and a parallel inhibition of Uch-L1 and TREM2, both in vitro and in vivo, in Tg 5XFAD and in human brains of sporadic AD. This mechanism creates a synergistic loop that fosters inflammation. We also demonstrated a significant protection exerted by the restoration of Uch-L1 activity. The rescue of the enzyme is able to abolish the decrease of TREM2 and the parameters of neuroinflammation.
Keywords:
Alzheimer’s disease; NF-kB pathway; TREM2; Uch-L1; neuroinflammation; stroke.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Amyloid Precursor Protein Secretases / biosynthesis
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Amyloid Precursor Protein Secretases / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Aspartic Acid Endopeptidases / biosynthesis
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Aspartic Acid Endopeptidases / genetics
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Brain Ischemia / complications
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Brain Ischemia / genetics
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Brain Ischemia / metabolism
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Cells, Cultured
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Cytokines / biosynthesis
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Down-Regulation
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Female
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Humans
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Inflammation / etiology
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Inflammation / metabolism*
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Male
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Membrane Glycoproteins / metabolism*
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Mice
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NF-kappa B / metabolism
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Neurons / metabolism
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Peptide Fragments / metabolism*
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Receptors, Immunologic / metabolism*
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Stroke / complications
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Stroke / genetics
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Stroke / metabolism*
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Ubiquitin Thiolesterase / metabolism*
Substances
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Amyloid beta-Peptides
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Cytokines
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Membrane Glycoproteins
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NF-kappa B
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Peptide Fragments
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Receptors, Immunologic
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Trem2 protein, mouse
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Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
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amyloid beta-protein (1-42)
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Amyloid Precursor Protein Secretases
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Ubiquitin Thiolesterase
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse