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Neurobiol Dis. 2019 Apr 2;127:432-448. doi: 10.1016/j.nbd.2019.02.015. [Epub ahead of print]

Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis.

Author information

1
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Veterans Affairs Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, University of California, Los Angeles (UCLA), United States of America; Alzheimer's Translational Center, Veterans Administration (Research 151), Bldg. 114, Rm. 114-1, 11301 Wilshire Blvd, Los Angeles, CA 90073, United States of America. Electronic address: bteter@ucla.edu.
2
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Veterans Affairs Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, University of California, Los Angeles (UCLA), United States of America. Electronic address: moriha@psy.med.osaka-u.ac.jp.
3
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Veterans Affairs Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, University of California, Los Angeles (UCLA), United States of America.
4
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America.
5
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Medicine, University of California, Los Angeles (UCLA), United States of America.
6
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Medicine, University of California, Los Angeles (UCLA), United States of America; Departments of Veterans Affairs Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, University of California, Los Angeles (UCLA), United States of America. Electronic address: sfrautschy@mednet.ucla.edu.
7
Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Medicine, University of California, Los Angeles (UCLA), United States of America; Departments of Veterans Affairs Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, University of California, Los Angeles (UCLA), United States of America. Electronic address: gregorycole@mednet.ucla.edu.

Abstract

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

KEYWORDS:

Alzheimer's disease; Amyloid; Amyloid vaccine; CD33; Innate immune; Phagocytosis; TREM2

PMID:
30951849
DOI:
10.1016/j.nbd.2019.02.015

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