Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia.
Ontology highlight
ABSTRACT:
SUBMITTER: Grathwohl SA
PROVIDER: S-EPMC4721582 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
Publications
Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia.
Grathwohl Stefan A SA Kälin Roland E RE Bolmont Tristan T Prokop Stefan S Winkelmann Georg G Kaeser Stephan A SA Odenthal Jörg J Radde Rebecca R Eldh Therese T Gandy Sam S Aguzzi Adriano A Staufenbiel Matthias M Mathews Paul M PM Wolburg Hartwig H Heppner Frank L FL Jucker Mathias M
Nature neuroscience 20091018 11
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. ...[more]
Similar Datasets
Project description:Soluble amyloid-β (Aβ) is considered to be a critical component in the pathogenesis of Alzheimer's disease (AD). Evidence suggests that these non-fibrillar Aβ assemblies are implicated in synaptic dysfunction, neurodegeneration and cell death. However, characterization of these species comes mainly from studies in cellular or animal models, and there is little data in intact human samples due to the lack of adequate optical microscopic resolution to study these small structures. Here, to achieve super-resolution in all three dimensions, we applied Array Tomography (AT) and Stimulated Emission Depletion microscopy (STED), to characterize in postmortem human brain tissue non-fibrillar Aβ structures in amyloid plaques of cases with autosomal dominant and sporadic AD. Ultrathin sections scanned with super-resolution STED microscopy allowed the detection of small Aβ structures of the order of 100 nm. We reconstructed a whole human amyloid plaque and established that plaques are formed by a dense core of higher order Aβ species (~0.022 µm3) and a peripheral halo of smaller Aβ structures (~0.003 µm3). This work highlights the potential of AT-STED for human neuropathological studies.
| S-EPMC6435662 | biostudies-literature
Project description:Amyloid plaques are a pathological hallmark of Alzheimer's disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer's disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer's disease.
| S-EPMC7725705 | biostudies-literature
Project description:Many lines of evidence support that ?-amyloid (A?) peptides play an important role in Alzheimer's disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how A? contributes to AD remain unclear. While A? is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in A? has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting A? have not shown the hoped-for benefits. Thus, doubts have been growing about the role of A? as a therapeutic target. Here we review evidence supporting the involvement of A? in AD, highlight the importance of differentiating between various forms of A?, and suggest that a better understanding of A?'s precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.
| S-EPMC4322079 | biostudies-other
Project description:Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
| S-EPMC8043951 | biostudies-literature
Project description:Two microglial TAM receptor tyrosine kinases, Axl and Mer, have been linked to Alzheimer's disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer's disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia was coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer's disease, genetic ablation of Axl and Mer resulted in microglia that were unable to normally detect, respond to, organize or phagocytose amyloid-β plaques. These major deficits notwithstanding, TAM-deficient APP/PS1 mice developed fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development.
| S-EPMC8102389 | biostudies-literature
Project description:Amyloid-beta peptides which aggregate and accumulate in Alzheimer’s disease (AD) brain are known to have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration and dityrosine cross-linking. Here we add to the list of PTM citrullination (deimination) of Arg5 residue in plaque-derived Abeta in sporadic AD brains, identified by tandem mass spectrometry. We quantitated the level of citrullination on multiple N-truncated Abeta isoforms present in plaque-associated fractions and found that almost 30 % of pyroGlu3-Abeta pool was citrullinated in plaques from AD temporal cortex. We also documented citrullinated Abeta peptides in the detergent insoluble fractions from AD frontal cortex with ~ 22 % citrullination in the pyroGlu3-Abeta pool. Citrullination of Abeta is a common PTM, closely associated with pyroglutamate-Abeta formation and Abeta accumulation in AD. This may have implications for Abeta toxicity, auto-antigenicity of Abeta, and may be relevant for the design of diagnostic assays and therapeutic targeting.
2021-11-24 | PXD025620 | Pride
Project description:BACKGROUND:Soluble beta-amyloid (A?) can be cleared from the brain through various mechanisms including enzymatic degradation, glial cell phagocytosis, transport across the blood-brain barrier, and glymphatic clearance. However, the relative contribution of each clearance system and their compensatory effects in delaying the pathological process of Alzheimer's disease (AD) are currently unknown. METHODS:Fluorescent trace, immunofluorescence, and Western blot analyses were performed to compare glymphatic clearance ability and A? accumulation among 3-month-old APP695/PS1-dE9 transgenic (APP/PS1) mice, wild-type mice, aquaporin 4 knock out (AQP4-/-) mice, and AQP4-/-/APP/PS1 mice. The consequence of selectively eliminating microglial cells, or downregulating apolipoprotein E (apoE) expression, on A? burden, was also investigated in the frontal cortex of AQP4-/-/APP/PS1 mice and APP/PS1 mice. RESULTS:AQP4 deletion in APP/PS1 mice significantly exaggerated glymphatic clearance dysfunction, and intraneuronal accumulation of A? and apoE, although it did not lead to A? plaque deposition. Notably, microglia, but not astrocytes, increased activation and phagocytosis of A? in the cerebral cortex of AQP4-/-/APP/PS1 mice, compared with APP/PS1 mice. Selectively eliminating microglia in the frontal cortex via local injection of clodronate liposomes resulted in deposition of A? plaques in AQP4-/-/APP/PS1 mice, but not APP/PS1 mice. Moreover, knockdown of apoE reduced intraneuronal A? levels in both APP/PS1 mice and AQP4-/-/APP/PS1 mice, indicating an inhibitory effect of apoE on A? clearance. CONCLUSION:The above results suggest that the glymphatic system mediated A? and apoE clearance and microglia mediated A? degradation synergistically prevent A? plague formation in the early stages of the AD mouse model. Protecting one or both of them might be beneficial to delaying the onset of AD.
| S-EPMC7532614 | biostudies-literature
Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.
2021-02-25 | GSE160523 | GEO
Project description:Specificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid-β (Aβ) deposits is high for detection of neuritic Aβ plaques, a mature form of Aβ deposits which often have dense Aβ core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffuse Aβ plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheimer's disease (AD). Relative contributions of different plaque types to amyloid PET signal is unclear, particularly in neocortical areas where they are intermixed in AD. In vitro binding assay and autoradiography were performed using [3H]flutemetamol and [3H]Pittsburgh Compound-B (PiB) in frozen brain homogenates from 30 autopsy cases including sporadic AD and non-AD controls with a range of brain Aβ burden and plaque density. Fixed tissue sections of frontal cortex and caudate from 10 of the AD cases were processed for microscopy using fluorescent derivatives of flutemetamol (cyano-flutemetamol) and PiB (cyano-PiB) and compared to Aβ immunohistochemistry and pan-amyloid (X-34) histology. Using epifluorescence microscopy, percent area coverage and fluorescence output values of cyano-PiB- and cyano-flutemetamol-labeled plaques in two-dimensional microscopic fields were then calculated and combined to obtain integrated density measurements. Using confocal microscopy, we analysed total fluorescence output of the entire three-dimensional volume of individual cored plaques and diffuse plaques labeled with cyano-flutemetamol or cyano-PiB. [3H]Flutemetamol and [3H]PiB binding values in tissue homogenates correlated strongly and their binding pattern in tissue sections, as seen on autoradiograms, overlapped the pattern of Aβ-immunoreactive plaques on directly adjacent sections. Cyano-flutemetamol and cyano-PiB fluorescence was prominent in cored plaques and less so in diffuse plaques. Across brain regions and cases, percent area coverage of cyano-flutemetamol-labeled plaques correlated strongly with cyano-PiB-labeled and Aβ-immunoreactive plaques. For both ligands, plaque burden, calculated as percent area coverage of all Aβ plaque types, was similar in frontal cortex and caudate regions, while integrated density values were significantly greater in frontal cortex, which contained both cored plaques and diffuse plaques, compared to the caudate, which contained only diffuse plaques. Three-dimensional analysis of individual plaques labeled with either ligand showed that total fluorescence output of a single cored plaque was equivalent to total fluorescence output of approximately three diffuse plaques of similar volume. Our results indicate that [18F]flutemetamol and [11C]PiB PET signal is influenced by both diffuse plaques and cored plaques, and therefore is likely a function of plaque size and density of Aβ fibrils in plaques. Brain areas with large volumes/frequencies of diffuse plaques could yield [18F]flutemetamol and [11C]PiB PET retention levels comparable to brain regions with a lower volume/frequency of cored plaques.
| S-EPMC7498488 | biostudies-literature
Project description:Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.
| S-EPMC3264491 | biostudies-other