The neuroimmune system in Alzheimer's disease: the glass is half full

Abstract

It is well established that microglia, the neuroimmune cells of the brain, are associated with amyloid-β (Aβ) deposits in Alzheimer's disease (AD). However, the roles of these cells and other mononuclear phagocytes such as monocytes and macrophages in AD pathogenesis and progression have been elusive. Clues to mononuclear phagocyte involvement came with the demonstration that Aβ directly activates microglia and monocytes to produce neurotoxins, signifying that a receptor mediated interaction of Aβ with these cells may be critical for neurodegeneration seen in AD. Also, in AD brain, mononuclear phagocyte distribution changes from a uniform pattern that covers the brain parenchyma to distinct clusters intimately associated with areas of Aβ deposition, but the driving force behind this choreography was unclear. Here, we review our recent work identifying mononuclear phagocyte receptors for Aβ and unraveling mechanisms of recruitment of these cells to areas of Aβ deposition. While our findings and those of others have added significantly to our understanding of the role of the neuroimmune system in AD, the glass remains half full (or half empty) and a lot remains to be uncovered.

Fig. 1.

Increased brain Aβ levels in CCR2-deficient AβPP mice is associated with perivascular Aβ deposition. A) Aβ₄₂ levels were measured by ELISA (each data point is mean ± SEM, n = 3–6 per group, *p < 0.004). b) Immunohistochemistry with anti-Aβ and control antibodies showing perivascular Aβ deposition (arrowheads) in 65 day old APP-CCR2^−/− mice.

Fig. 2.

Reduced expression of Scara1 Aβ-binding receptor in microglia from old transgenic PS1-APP mice. Expression of Scara1 in CD11b⁺ cells was compared between transgenic PS1-APP mice and their age-matched WT littermates at 1.5, 3, 8, and 14 months of age. At 8 and 14 months of age, PS1-APP transgenic mice show significantly reduced expression of Scara1 compared with their WT littermates. (*p < 0.05).