Formation and maintenance of Alzheimer's disease A-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.

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    • "To investigate the effects of replacing brain-resident myeloid cells with peripheral monocytes during cerebral -amyloidosis, we crossed APPPS1 mice, which develop first amyloid deposits at 6–8 wk of age (Radde et al., 2006), with the CD11b- HSVTK (TK) line (Heppner et al., 2005). TK mice express herpes simplex thymidine kinase in myeloid cells, which allows for myeloid cell ablation through a 2-wk intracerebroventricular (icv) ganciclovir (GCV) administration in wild-type as well as APPPS1 mice (Grathwohl et al., 2009; Varvel et al., 2012). Importantly, we have previously shown that upon discontinuation of GCV administration, peripheral monocytes repopulate the entire brain within 2 wk (either using eGFP bone marrow reconstitution or an irradiation-independent model, i.e., animals expressing red fluorescent protein under the inflammatory monocyte-specific chemokine receptor-2 promoter; Varvel et al., 2012). "
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    ABSTRACT: Immune cells of myeloid lineage are encountered in the Alzheimer's disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.
    No preview · Article · Oct 2015 · Journal of Experimental Medicine
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    • "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). "
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    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.
    Full-text · Article · Mar 2015 · Experimental Gerontology
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    • "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 "
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    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.
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