Alzheimer Disease: El Khoury J

El Khoury J, Luster AD. · Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Trends Pharmacol Sci. · Pubmed #18835047 No free full text.

Abstract: In Alzheimer's disease (AD), and other conditions affecting integrity of the blood-brain barrier, microglia can originate in the bone marrow, migrate into the blood and enter the brain in a chemokine-dependent manner. CCR2, a chemokine receptor that controls mononuclear phagocyte infiltration into the brain in multiple sclerosis, bacterial meningitis and neuropathic pain, also regulates microglia accumulation in mouse models of AD. CCR2 deficiency leads to lower microglia accumulation and higher brain beta-amyloid (Abeta) levels, indicating that early microglial accumulation promotes Abeta clearance. In support of this protective role, enhancing microglia accumulation delays progression of AD. AD mice that constitutively express interleukin-1 in the brain, or that are deficient in peripheral mononuclear phagocyte transforming growth factor-beta signaling, have increased microglia accumulation around beta-amyloid plaques and reduced AD-like pathology. Regulating microglia recruitment into the brain is a novel therapeutic strategy to delay or stop progression of AD. Here, we review the role of microglia in AD and the mechanisms of their accumulation and discuss implications for AD therapy.

Hickman SE, Allison EK, El Khoury J. · Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, and Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129. · J Neurosci. · Pubmed #18701698 links to  free full text

Abstract: Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Abeta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Abeta-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1beta (interleukin-1beta) and tumor necrosis factor alpha (TNFalpha), suggesting that there is an inverse correlation between cytokine production and Abeta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFalpha decreased the expression of SRA and CD36 and reduced Abeta uptake. Our data indicate that, although early microglial recruitment promotes Abeta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Abeta deposition downregulate genes involved in Abeta clearance and promote Abeta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.

El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. · Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA. · Nat Med. · Pubmed #17351623 No free full text.

Abstract: Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.