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

Autor: Sally A. Frautschy, Giselle P. Lim, T. Chu, Mychica Jones, Xiaohong Zuo, R.M. Paul, Greg M. Cole, B. Teter, Takashi Morihara
Rok vydání: 2019
Předmět:
0301 basic medicine
Aging
Sialic Acid Binding Ig-like Lectin 3
Anti-Inflammatory Agents
Gene Expression
Syk
Plaque
Amyloid
Neurodegenerative
Alzheimer's Disease
Transgenic
Mice
Amyloid beta-Protein Precursor
chemistry.chemical_compound
0302 clinical medicine
Immunologic
Receptors
TREM2
Innate
2.1 Biological and endogenous factors
Receptors
Immunologic
Aetiology
Plaque
Membrane Glycoproteins
Microglia
Anti-Inflammatory Agents
Non-Steroidal
Brain
Alzheimer's disease
medicine.anatomical_structure
Neurology
Neurological
Disease Progression
Innate immune
Non-Steroidal
Genetically modified mouse
Amyloid
Curcumin
Clinical Sciences
Mice
Transgenic
Biology
Article
lcsh:RC321-571
03 medical and health sciences
Amyloid vaccine
Phagocytosis
Alzheimer Disease
Complementary and Integrative Health
Acquired Cognitive Impairment
Genetics
medicine
Animals
Humans
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Neuroinflammation
Neurology & Neurosurgery
Innate immune system
Animal
Prevention
Immunity
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Immunity
Innate
Brain Disorders
Disease Models
Animal
030104 developmental biology
chemistry
Disease Models
Cancer research
Dementia
CD33
030217 neurology & neurosurgery
Zdroj: Neurobiol Dis
Neurobiology of Disease, Vol 127, Iss, Pp 432-448 (2019)
ISSN: 0969-9961
Popis: 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.
Databáze: OpenAIRE
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