APOE genotype and sex affect microglial interactions with plaques in Alzheimer\u2019s disease mice

T L Stephen,T E Morgan,C J Pike,D Balu,M J Ladu,M Cacciottolo,C E Finch

doi:10.1186/s40478-019-0729-z

Abstract

Microglia affect Alzheimer’s disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E (APOE) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across APOE3 and APOE4 genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male APOE3 mice with significant reductions in coverage observed with both APOE4 genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which APOE4 genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male APOE3 mice and reduced by APOE4 genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with APOE4 genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with APOE4 genotype and female sex.

Highlights

The neuropathology of Alzheimer’s disease (AD) is characterized primarily by the region-specific accumulation of amyloid beta (Aβ) into senile plaques and hyperphosphorylated tau into neurofibrillary tangles
apolipoprotein E (APOE) genotype and sex are associated with microglial interactions with amyloid plaques To explore the effects of APOE genotype and sex on interactions of microglia with amyloid plaques, high-resolution confocal images were used to capture microglia associated with Thioflavin S (ThioS)-labeled deposits in EFAD mice (Fig. 1a)
We examined whether APOE genotype and/or sex affect the levels and cellular localization of triggering receptor expressed on myeloid cells 2 (TREM2) within microglia using HPC sections immunolabeled for TREM2 and ionized calcium binding adaptor molecule 1 (Iba1) and counterstained with ThioS (Fig. 3a)

Summary

Introduction

The neuropathology of AD is characterized primarily by the region-specific accumulation of amyloid beta (Aβ) into senile plaques and hyperphosphorylated tau into neurofibrillary tangles. Both plaques and tangles are widely hypothesized to contribute to the neurodegenerative changes that occur in AD and manifest clinically as dementia [56]. AD neuropathology involves several other significant components, including microglial activation, that are associated with disease progression. While it has long been known that activated microglia co-localize with Aβ plaques [20], as noted by Alzheimer himself [47], their roles remain incompletely defined. The regulation of microglial-plaque associations is a topic of high importance. TREM2 activation is essential for immune function in the brain, promoting

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