Infiltrating Hematogenous Macrophages Aggregate Around β-Amyloid Plaques in an Age- and Sex-Dependent Manner in a Mouse Model of Alzheimer Disease

Abstract

b-Amyloid (Ab) 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/) from hematogenous macrophages (hM/), as they are morphologically and phenotypically similar when activated. To distinguish between mM/ and hM/ 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/, but not in mM/. These mice were crossed with 5XFAD mice. The offspring demonstrated robust AD pathology and enabled visual discrimination of mM/ from hM/. Mutant mice demonstrated robust increases in Ab1–42, area of Ab plaques, gliosis and deficits in spatial learning by age 5 months. The time-course of Ab accumulation, paralleled by the accumulation of hM/ around Ab plaques, was more robust in female compared with male mice and preceded behavioral changes. Thus, the accumulation of infiltrating hM/ around Ab plaques was age- and sex-dependent and preceded cognitive impairment.