Stroke and Amyloid-β Downregulate TREM-2 and Uch-L1 Expression that Synergistically Promote the Inflammatory Response

J Alzheimers Dis. 2019;71(3):907-920. doi: 10.3233/JAD-190494.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyloid Precursor Protein Secretases / biosynthesis
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / biosynthesis
  • Aspartic Acid Endopeptidases / genetics
  • Brain Ischemia / complications
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Down-Regulation
  • Female
  • Humans
  • Inflammation / etiology
  • Inflammation / metabolism*
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • NF-kappa B / metabolism
  • Neurons / metabolism
  • Peptide Fragments / metabolism*
  • Receptors, Immunologic / metabolism*
  • Stroke / complications
  • Stroke / genetics
  • Stroke / metabolism*
  • Ubiquitin Thiolesterase / metabolism*

Substances

  • Amyloid beta-Peptides
  • Cytokines
  • Membrane Glycoproteins
  • NF-kappa B
  • Peptide Fragments
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases
  • Ubiquitin Thiolesterase
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse