Dataset Information

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

ABSTRACT: Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.

SUBMITTER: Tzioras M

PROVIDER: S-EPMC10518633 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

Tzioras Makis M Daniels Michael J D MJD Davies Caitlin C Baxter Paul P King Declan D McKay Sean S Varga Balazs B Popovic Karla K Hernandez Madison M Stevenson Anna J AJ Barrington Jack J Drinkwater Elizabeth E Borella Julia J Holloway Rebecca K RK Tulloch Jane J Moss Jonathan J Latta Clare C Kandasamy Jothy J Sokol Drahoslav D Smith Colin C Miron Veronique E VE Káradóttir Ragnhildur Thóra RT Hardingham Giles E GE Henstridge Christopher M CM Brennan Paul M PM McColl Barry W BW Spires-Jones Tara L TL

Cell reports. Medicine 20230830 9

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. ...[more]

PMID: 37652017

Similar Datasets

Project description:Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.

Dataset Information

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

Publications

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets