Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer’s disease

Sideris, Dimitrios I; Danial, John S. H.; Emin, Derya; Ruggeri, Francesco Simone; Xia, Zengjie; Zhang, Yu P; Lobanova, Evgeniia; Dakin, Helen; De, Suman; Miller, Aline F.; Sang, Jason C.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Fraser, Graham; Crowther, Damian C.; Klenerman, David

doi:10.1093/braincomms/fcab147

Cited by 44 publications

(59 citation statements)

References 63 publications

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“…aggregates from controls, which are larger on average, would be less inflammatory. This result is similar to the result of our recent study on a Braak stage III AD brains, where we found that the hippocampus contained a higher proportion of smaller aggregates than the visual association cortex and that these hippocampal aggregates caused an increased inflammatory response 59 .…”

Section: Discussionsupporting

confidence: 92%

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Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

et al. 2022

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Soluble α-synuclein aggregates varying in size, structure, and morphology have been closely linked to neuronal death in Parkinson’s disease. However, the heterogeneity of different co-existing aggregate species makes it hard to isolate and study their individual toxic properties. Here, we show a reliable non-perturbative method to separate a heterogeneous mixture of protein aggregates by size. We find that aggregates of wild-type α-synuclein smaller than 200 nm in length, formed during an in vitro aggregation reaction, cause inflammation and permeabilization of single-liposome membranes and that larger aggregates are less toxic. Studying soluble aggregates extracted from post-mortem human brains also reveals that these aggregates are similar in size and structure to the smaller aggregates formed in aggregation reactions in the test tube. Furthermore, we find that the soluble aggregates present in Parkinson’s disease brains are smaller, largely less than 100 nm, and more inflammatory compared to the larger aggregates present in control brains. This study suggests that the small non-fibrillar α-synuclein aggregates are the critical species driving neuroinflammation and disease progression.

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Section: Discussionsupporting

confidence: 92%

“…Coverslip preparation was done as described previously 59,62,63 . Afterwards the coverslip was passivated with neutravidin (0.2 mg/mL) diluted in 0.05% PBS-T(v/v) (tween20 Cat.…”

Section: Single-molecule Super-resolution Imagingmentioning

confidence: 99%

Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

et al. 2022

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“…Here, we circumvent these multiple drawbacks by using a human microglia xenotransplantation model 22,23 . We provide a full map of the different cell states adopted by human microglia in response to amyloid-b pathology, including the elusive component of soluble oligomeric amyloid-β that have been linked to neuroinflammation, neurodegeneration and cognitive impairment [24][25][26][27] . We show that human microglia react very differently from mouse microglia to amyloid-b pathology.…”

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confidence: 99%

A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology

Mancuso

Fattorelli

Martínez-Muriana

et al. 2022

Preprint

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Microglial activation and neuroinflammation are initial steps in the pathogenesis of Alzheimer's disease (AD). However, studies in mouse models and human postmortem samples have yielded divergent results regarding microglia cell states relevant to AD. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for early AD. While human microglia adopt a disease-associated (DAM) profile, they display a much more pronounced HLA-cell state related to antigen presentation in response to amyloid plaques. In parallel, a distinctive pro-inflammatory cytokine and chemokine CRM response is mounted against oligomeric amyloid-β. TREM2 and, to a lesser extent, APOE polymorphisms, modulate the response of microglia to amyloid-b plaques, in contrast with the response to oligomeric Aβ. Specific polygenic risk genes are enriched in each branch of these multi-pronged response of human microglia to amyloid pathology (ARM). ARM responses can be captured in post-mortem studies when reanalyzed in light of this novel, comprehensive data set. In conclusion, therapeutic strategies targeting microglia in AD need to carefully assess how they affect the different cell states, as the overall balance between distinct microglial profiles might determine a protective or damaging outcome.

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“…The aggregates of Aβ can be of different size and solubility, ranging from small soluble dimers and trimers to the intermediate soluble species (termed as oligomers and protofibrils) and to finally insoluble fibrils, which constitute the core components of the amyloid-plaques [1][2][3]. Different Aβ aggregates exhibit distinct toxicity mechanisms, with a growing body of evidence suggesting a correlation of oligomers and protofibrils with the neuronal and synaptic damage observed in AD [4][5][6]. Due to their small size and high mobility, soluble oligomers of Aβ are more likely to exert their neurotoxic effects through their ability to permeabilize and cross cell membranes [7,8], while the slightly larger protofibrils have been shown to induce toxicity by other mechanisms, for example, by enhancing neuroinflammation [7].…”

Section: Introductionmentioning

confidence: 99%

A Brain-Targeting Bispecific-Multivalent Antibody Clears Soluble Amyloid-Beta Aggregates in Alzheimer's Disease Mice

et al. 2022

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Amyloid-β (Aβ) oligomers and protofibrils are suggested to be the most neurotoxic Aβ species in Alzheimer’s disease (AD). Hence, antibodies with strong and selective binding to these soluble Aβ aggregates are of therapeutic potential. We have recently introduced HexaRmAb158, a multivalent antibody with additional Aβ-binding sites in the form of single-chain fragment variables (scFv) on the N-terminal ends of Aβ protofibril selective antibody (RmAb158). Due to the additional binding sites and the short distance between them, HexaRmAb158 displayed a slow dissociation from protofibrils and strong binding to oligomers in vitro. In the current study, we aimed at investigating the therapeutic potential of this antibody format in vivo using mouse models of AD. To enhance BBB delivery, the transferrin receptor (TfR) binding moiety (scFv8D3) was added, forming the bispecific-multivalent antibody (HexaRmAb158-scFv8D3). The new antibody displayed a weaker TfR binding compared to the previously developed RmAb158-scFv8D3 and was less efficiently transcytosed in a cell-based BBB model. HexaRmAb158 detected soluble Aβ aggregates derived from brains of tg-ArcSwe and AppNL−G−F mice more efficiently compared to RmAb158. When intravenously injected, HexaRmAb158-scFv8D3 was actively transported over the BBB into the brain in vivo. Brain uptake was marginally lower than that of RmAb158-scFv8D3, but significantly higher than observed for conventional IgG antibodies. Both antibody formats displayed similar brain retention (72 h post injection) and equal capacity in clearing soluble Aβ aggregates in tg-ArcSwe mice. In conclusion, we demonstrate a bispecific-multivalent antibody format capable of passing the BBB and targeting a wide-range of sizes of soluble Aβ aggregates.

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Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer’s disease

Cited by 44 publications

References 63 publications

Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology

A Brain-Targeting Bispecific-Multivalent Antibody Clears Soluble Amyloid-Beta Aggregates in Alzheimer's Disease Mice

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