Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer's disease-like mice

Although central nervous system-resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-beta (A beta), a major pathological hallmark of Alzheimer's disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater A beta-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce A beta plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in A beta-carrying APPPS1 mice crossed to TK mice (APPPS1; TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in A beta burden or APP processing in APPPS1; TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around A beta deposits. Even additional anti-A beta antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered A beta burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing A beta burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell-based therapies for AD.