Infiltrating Hematogenous Macrophages Aggregate Around Beta-Amyloid Plaques In An Age- And Sex-Dependent Manner In A Mouse Model Of Alzheimer Disease

beta-Amyloid (A beta) plaques can trigger chronic inflammation in the cellular environment that recruits infiltrating macrophages during the course of Alzheimer disease (AD). Activated macrophages release pro-inflammatory cytokines that increase neurotoxicity associated with AD. A major impediment to investigating neuroinflammation involving macrophage activity is the inability to discriminate resident microglial macrophages (mM phi) from hematogenous macrophages (hM phi), as they are morphologically and phenotypically similar when activated. To distinguish between mM phi and hM phi and to determine their respective roles in chronic inflammation associated with the progression of amyloidosis, we used lysEGFP-ki transgenic mice that express enhanced green fluorescent protein in hM phi, but not in mM phi. These mice were crossed with 5XFAD mice. The offspring demonstrated robust AD pathology and enabled visual discrimination of mM phi from hM phi. Mutant mice demonstrated robust increases in A beta(1-42), area of A beta plaques, gliosis and deficits in spatial learning by age 5 months. The time-course of A beta accumulation, paralleled by the accumulation of hM phi around A beta plaques, was more robust in female compared with male mice and preceded behavioral changes. Thus, the accumulation of infiltrating hM phi around A beta plaques was age- and sex-dependent and preceded cognitive impairment.