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The Journal of Neuroscience, August 13, 2008, 28(33):8354-8360; doi:10.1523/JNEUROSCI.0616-08.2008

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Neurobiology of Disease
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice

Suzanne E. Hickman,¹ Elizabeth K. Allison,¹ and Joseph El Khoury^1,2

¹Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, and ²Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

Correspondence should be addressed to Dr. Joseph El Khoury, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, CNY 149, Room 8301, 149 13th Street, Charlestown, MA 02129. Email: jelkhoury{at}partners.org

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of β-amyloid (Aβ) before formation of senile plaques. However, persistent Aβ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Aβ may decrease with age and progression of AD pathology. To determine the effects of aging and Aβ deposition on microglial ability to clear Aβ, 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 Aβ-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Aβ-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-1β (interleukin-1β) and tumor necrosis factor (TNF), suggesting that there is an inverse correlation between cytokine production and Aβ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNF decreased the expression of SRA and CD36 and reduced Aβ uptake. Our data indicate that, although early microglial recruitment promotes Aβ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Aβ deposition downregulate genes involved in Aβ clearance and promote Aβ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.

Key words: microglia; Alzheimer's disease; transgenic mice; amyloid; phagocytosis; degradation

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Received Feb. 11, 2008; revised June 11, 2008; accepted July 15, 2008.

Correspondence should be addressed to Dr. Joseph El Khoury, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, CNY 149, Room 8301, 149 13th Street, Charlestown, MA 02129. Email: jelkhoury{at}partners.org

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