Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia

Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Nature Neuroscience (Impact Factor: 16.1). 11/2009; 12(11):1361-3. DOI: 10.1038/nn.2432
Source: PubMed


In Alzheimer's disease, microglia cluster around beta-amyloid deposits, suggesting that these cells are important for amyloid plaque formation, maintenance and/or clearance. We crossed two distinct APP transgenic mouse strains with CD11b-HSVTK mice, in which nearly complete ablation of microglia was achieved for up to 4 weeks after ganciclovir application. Neither amyloid plaque formation and maintenance nor amyloid-associated neuritic dystrophy depended on the presence of microglia.

58 Reads
  • Source
    • "However, the role of these cells is somewhat complex. On one side, data indicates that microglia are poor phagocytes of Aβ and thus cannot play a significant role in Aβ clearance or plaque remodeling, either promoting or protecting against Aβ-induced pathology (Gate et al., 2010; Grathwohl et al., 2009). On the other side, reports indicate that microglial cells are capable of remodeling and enhancing the clearance of Aβ plaques (Chakrabarty et al., 2010; Gate et al., 2010; Kiyota et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease that leads to the progressive deterioration of cognitive and memory function. The deposition of extracellular beta-amyloid (Aβ) senile plaques and intracellular tau neurofibrillary tangles are considered the cardinal pathological hallmarks of AD, however, accumulating evidence indicates that immune cells may also play an important role in disease pathogenesis. Among these immune cells, blood-derived cells and their infiltration into the CNS towards Aβ plaques has been implicated in therapeutic strategies against AD. Here, we review the current literature on blood cell migration into the AD brain and the important players involved in this selective migration towards Aβ plaques. Copyright © 2015. Published by Elsevier Inc.
    Experimental Gerontology 03/2015; 219. DOI:10.1016/j.exger.2015.03.002 · 3.49 Impact Factor
  • Source
    • "One of the many effects of Ab deposition is the induction of reactive microgliosis, which involves the expansion of microglia and conversion to an activated state (Ransohoff and Cardona, 2010). Microgliosis predominantly involves the proliferation of brain-resident microglia, with some contribution from blood-borne monocytes and microglia migrating from adjacent non-damaged brain areas (El Khoury et al., 2007; Grathwohl et al., 2009; Malm et al., 2005; Mildner et al., 2011; Simard et al., 2006; Stalder et al., 2005). To evaluate the impact of TREM2 deficiency on Ab-induced microglial responses in 5XFAD mice, we examined transcriptional profiles of microglia purified from 5XFAD and Trem2 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; DOI:10.1016/j.cell.2015.01.049 · 32.24 Impact Factor
  • Source
    • "Our results indicate that GPR84 influences neither the formation or elimination of b-amyloid plaques, nor the concentration of soluble Ab42, one of the most abundant and toxic form of b-amyloid. This is in agreement with previous studies showing that microglia do not affect the plaques (Grathwohl et al., 2009; Mildner et al., 2011) or at best modestly (Simard et al., 2006; Tahara et al., 2006; Naert and Rivest, 2011; Song et al., 2011). Furthermore , our results reveal a higher number of degenerating dendrites in the absence of GPR84, leading us to infer that a microglial response regulated by GPR84 is required to protect dendrites from further degeneration. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglia surrounds the amyloid plaques that form in the brains of patients with Alzheimer's disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, i.e., experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 01/2015; 46. DOI:10.1016/j.bbi.2015.01.010 · 5.89 Impact Factor
Show more