Macrophages in Alzheimer's disease: the blood-borne identity

Abstract

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-beta (Abeta) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting beta-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology.

Fig. 1

A confocal image of unmanipulated wild-type C57BL/6 mouse cerebral cortex showing presence of CD45⁺CD4⁺ cells in the parenchyma. Cortical layers are indicated by roman numerals and individual channels are shown with DAPI nuclear counterstain

Fig. 2

A schematic representation showing the roles of mononuclear phagocytes in Alzheimer’s disease. A penetrating cerebral artery is shown on the left, and a β-amyloid plaque within the brain parenchyma is shown to the right. Peripheral mononuclear phagocytes (macrophages) are infiltrating the brain parenchyma and homing to the β-amyloid plaque, where they phagocytose and clear deposited Aβ. Peripheral mononuclear phagocytes are depicted in green, brain-resident microglia are magenta, neurons are blue, and the β-amyloid plaque is shown in red