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 |
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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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