The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin

Abstract

Microglia, the innate immune cells of the central nervous system (CNS) survey their surroundingswith their cytoplasmic processes, phagocytose debris and rapidly respond to injury. These functions are affected by the presence of beta-Amyloid (Aβ) deposits, hallmark lesions of Alzheimer's disease (AD). We recently demonstrated that exchanging functionally altered endogenous microglia with peripheral myeloid cells did not change Aβ-burden in a mouse model mimicking aspects of AD at baseline, and only mildly reduced Aβ plaques upon stimulation. To better characterize these different myeloid cell populations, we used long-term in vivo 2-photon microscopy to compare morphology and basic functional parameters of brain populating peripherally-derived myeloid cells and endogenous microglia. While peripherally-derived myeloid cells exhibited increased process movement in the nondiseased brain, the Aβ rich environment in an AD-like mouse model, which induced an alteration of surveillance functions in endogenous microglia, also restricted functional characteristics and response to CNS injury of newly recruited peripherally-derived myeloid cells. Our data demonstrate that the Aβ rich brain environment alters the functional characteristics of endogenous microglia as well as newly recruited peripheral myeloid cells, which has implications for the role of myeloid cells in disease and the utilization of these cells in Alzheimer's disease therapy.Dementia caused by Alzheimer's disease (AD) currently affects over 35 million people worldwide 1 and is characterized by extracellular deposition of beta-Amyloid (Aβ), intracellular neurofibrillary Tau tangles and neurodegeneration 2,3 . The identification of microglia associated genes as risk factors for sporadic AD has highlighted the importance of microglia, the intrinsic immune cells of the central nervous system (CNS), in the disease process 4,5 . In the healthy brain microglia are surveying their environment with their fine, arborizing cytoplasmic processes, screening the entire brain parenchyma every few hours and rapidly responding to injury 6 . As a resident cell population with limited turnover 7 microglia functionality as measured by baseline motility of cytoplasmic

Disturbance of phylogenetic layer-specific adaptation of human brain gene expression in Alzheimer's disease

“…Although some pathways are present in more than one comparison, such as "extracellular matrix organisation" and "extracellular structure organisation" in both SUP with ALL and INF with ALL comparisons, they are represented by different genes, such as SFRP2 (in SUP with ALL) and MYH11, COL5A2, and COL8A1 (in INF with ALL), all up regulated in the ALL samples when compared to the others. This is also consistent with the cellular environment alterations caused by the accumulation of β-amyloid 38 .…”

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

“…Here, we demonstrate that replacing microglia with SVZ/WM-derived myeloid cells impedes plaque development in specific grey matter brain regions. Previous studies have shown that neither PND microglia repopulation nor replacement with monocytes has a significant impact on plaque pathogenesis 69,[89][90][91][92] , highlighting the significance of these SVZ/WM-derived myeloid cells in disease. An elegant study by Füger et al (2017) indicates that the accumulation of plaque-associated microglia derives from local microglial proliferation 93 , thus we postulate that it is unlikely that plaque-associated microglia derive or travel from the WM tracts in untreated AD brains.…”

Tools and Approaches for Studying Microglia In vivo

“…Time-lapse in vivo two-photon imaging of Cx3cr1 GFP mouse brains led to the seminal discovery that microglia are highly dynamic surveillants that constantly extend and retract their processes during homeostasis (3). Several studies have since used twophoton imaging to study microglial dynamism in CNS disease models and aging (66)(67)(68). Most two-photon microglia imaging studies are performed on mice under general anesthesia through either a cranial window or thinned skull preparation [reviewed in detail in (69)].…”