Distinct inflammatory phenotypes of microglia and monocyte‐derived macrophages in Alzheimer's disease models: effects of aging and amyloid pathology

Abstract

SummaryAlzheimer's disease (AD) is a neurodegenerative disease characterized by formation of amyloid‐β (Aβ) plaques, activated microglia, and neuronal cell death leading to progressive dementia. Recent data indicate that microglia and monocyte‐derived macrophages (MDM) are key players in the initiation and progression of AD, yet their respective roles remain to be clarified. As AD occurs mostly in the elderly and aging impairs myeloid functions, we addressed the inflammatory profile of microglia and MDM during aging in TgAPP/PS1 and TgAPP/PS1dE9, two transgenic AD mouse models, compared to WT littermates. We only found MDM infiltration in very aged mice. We determined that MDM highly expressed activation markers at basal state. In contrast, microglia exhibited an activated phenotype only with normal aging and Aβ pathology. Our study showed that CD14 and CD36, two receptors involved in phagocytosis, were upregulated during Aβ pathogenesis. Moreover, we observed, at the protein levels in AD models, higher production of pro‐inflammatory mediators: IL‐1β, p40, iNOS, CCL‐3, CCL‐4, and CXCL‐1. Taken together, our data indicate that microglia and MDM display distinct phenotypes in AD models and highlight the specific effects of normal aging vs Aβ peptides on inflammatory processes that occur during the disease progression. These precise phenotypes of different subpopulations of myeloid cells in normal and pathologic conditions may allow the design of pertinent therapeutic strategy for AD.

Distinct microglia profile in Creutzfeldt–Jakob disease and Alzheimer's disease is independent of disease kinetics

“…The abundance of TMEM119‐positive microglia in brains of rpAD patients suggest local activation of resident microglia, rather than the recruitment of MDMs to the brain, a finding that is in line with mouse studies . In contrast, our sCJD patients displayed marginal amounts of TMEM119‐positive microglia.…”

“…In contrast, in advanced stages of disease, and with increasing age, prolonged activation leads to loss of microglial homeostatic functions and acquisition of a proinflammatory phenotype . Thus, microglia actively participate in disease progression and neurodegeneration, rather than simply acting as bystanders, as previously assumed …”

Microglia in Alzheimer’s disease

“…Activated microglia along with immunoglobulins and complement components are closely associated with Aβ deposits in brains from AD patients and AD mouse models (58)(59)(60)(61)(62). For example, activated microglia in AD show increased proliferation (63,64) and increased expression of inflammatory markers such as CD36, CD14, CD11c, MHC-II, and iNOS (65,66), as well as markers of the M1 phenotype. However, a new phenotype of microglia, referred to as "dark microglia," was found in conditions such as chronic stress, including in the APP/PS1 mouse model of AD.…”

Unravelling the glial response in the pathogenesis of Alzheimer's disease

“…As the disease progresses, chronic activation results in substantial microglial proliferation, which can occur to a differing extent in specific brain regions (67). There is also an increase in the number and degree of expression of inflammatory genes (68). However, a potential contribution from infiltrating peripheral cells cannot be excluded because the blood-brain barrier is known to be compromised during disease (69)(70)(71)(72).…”