Affiliations: [a] Department of Medicine, UCLA/VA School of Medicine, Los Angeles, CA, USA | [b] The Institute for Brain Aging and Dementia, University of California Irvine, Irvine, CA, USA | [c] Department of Neurology, University of California Irvine, Irvine, CA, USA | [d] Department of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, CA, USA
Correspondence:
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Corresponding author: Milan Fiala, M.D., UCLA Oral Biology and Medicine, CHS 73-084, 10833 LeConte, Los Angeles, CA 90095-1668, USA. E-mail: fiala@mednet.ucla.edu
Abstract: Innate immunity provides the first line of defense by recognizing pathogen-associated microbial patterns and inducing key co-stimulatory molecules and cytokines, which activate the mechanisms of the adaptive immune response. Innate immune cells perform phagocytosis, which can clear pathogens and tissue waste products but may also contribute to tissue injury due to harmful side effects of inflammation. Genetic studies of APOE4, cytokine polymorphisms and overexpression of inflammatory genes suggest that chronic inflammation may have adverse effects in patients with sporadic Alzheimer's disease. However, a vaccine against amyloid-β induced beneficial clearance of amyloid-β deposits, possibly through Fc receptor-mediated stimulation of microglial and macrophage uptake. A reconciliation of these two pathogenetic mechanisms is crucial to future progress in immune diagnosis and effective therapy. This may be possible by extending our recent observations suggesting that phagocytosis of amyloid-β by macrophages is excellent in normal subjects but is deficient in most AD patients. Thus increased proinflammatory cytokine levels and activated microglia and macrophages in patients may be compensatory for defective clearance of amyloid-β. Consequently, therapeutic interventions that increase phagocytosis of amyloid-β might decrease brain inflammation as well as reduce inflammation-induced neurodegeneration. Finally, peripheral blood leukocytes are a superior model system for investigation of innate immune dysfunction in Alzheimer's disease.
