Dataset Information

Proteopathic tau seeds contain key similarities to mature paired helical filaments in Alzheimer disease

ABSTRACT: Proteopathic seeds are soluble species of aggregation prone molecules such as tau, that are competent to instruct endogenous proteins to undergo templated misfolding. Yet the idea of proteopathic seeds for tau is largely abstract, and the relationship of the seeds to the final fibrils that define the diseases has not been determined. We utilized mass spectrometry (MS), and in vitro bioassays to characterize the soluble tau species, derived from human Alzheimer brain, that are capable of inducing tau seeding in bioreporter cells and in vivo. Multiple post translational modifications (PTM) were identified by MS, including phosphorylations, acetylations, and ubiquitinations. While the patterns are quite similar to that of post translational modifications on insoluble paired helical filament preparations, the presence of fewer overall post translational modifications, and some unique modifications, distinguish soluble seed competent tau from filamentous tau in Alzheimer disease. Surprisingly, the presence of ubiquitin modifications on the soluble seed competent species correlates positively with bioactivity, and the stoichiometry of ubiquitin occupancy and other PTMs¬ correlate with the aggressiveness of clinical disease measured by age of onset and rapidity of progression. These results define the bioactive, seed competent tau species as being closely related to, but distinct from, mature paired helical filaments, and provide insight into the molecular features of tau PTMs that ultimately generate the bioactive conformation of tau present in Alzheimer disease (AD).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Christoph Schlaffner

LAB HEAD: Judith A. Steen

PROVIDER: PXD032192 | Pride | 2025-05-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20200821_MK_Hyman_HMW_1912_Re_Slot1-10_1_2463.zip	Other
	20200821_MK_Hyman_HMW_1971_Re_Slot1-11_1_2464.zip	Other
	20200821_MK_Hyman_HMW_2014_Re_Slot1-12_1_2465.zip	Other
	20200821_MK_Hyman_HMW_2017_Re_Slot1-13_1_2466.zip	Other
	20200821_MK_Hyman_HMW_2021_Re_Slot1-14_1_2467.zip	Other

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Publications

Alzheimer proteopathic tau seeds are biochemically a forme fruste of mature paired helical filaments.

Kumar Mukesh M Quittot Noé N Dujardin Simon S Schlaffner Christoph N CN Viode Arthur A Wiedmer Anne A Beerepoot Pieter P Chun Joshua E JE Glynn Calina C Fernandes Analiese R AR Donahue Cameron C Steen Judith A JA Hyman Bradley T BT

Brain : a journal of neurology 20240201 2

Aggregation prone molecules, such as tau, form both historically well characterized fibrillar deposits (neurofibrillary tangles) and recently identified phosphate-buffered saline (PBS) extract species called proteopathic seeds. Both can cause normal endogenous tau to undergo templated misfolding. The relationship of these seeds to the fibrils that define tau-related diseases is unknown. We characterized the aqueous extractable and sarkosyl insoluble fibrillar tau species derived from human Alzhe ...[more]

PMID: 38236720

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Project description:The abnormal higher-order assembly of tau protein in neurons and glia underlies a large group of neurodegenerative diseases, including Alzheimer's disease (AD). Tau assemblies are first detected in localised brain regions and subsequently accumulate in connected networks. Prion-like propagation is thought to underlie the temporospatial accumulation of assembled tau, encompassing intracellular trafficking and trans-synaptic transfer of assembled tau species that seed the assembly of normally folded tau. Evidence suggests that extracellular vesicles (EVs), a diverse group of lipid vesicles that facilitate the intercellular transfer of bioactive molecules, mediate transfer of assembled tau seeds. However, the molecular species of assembled tau seeds in human brain are unknown. Furthermore, the identities of the EVs that mediate intercellular transfer of assembled tau and how this is achieved have not been determined. Here, we isolated sub-populations of EVs from human brain enriched in plasma membrane; endo-lysosomal; or mitochondrial proteins. We used electron cryo-tomography (cryo-ET) and single-particle electron cryo-microscopy (cryo-EM) to directly analyse the structure and molecular organisation of assembled tau seeds associated with intact EVs isolated from the brains of individuals who had AD. We found that short tau paired helical filaments (PHFs) were packaged within the lumen of large EVs enriched in endo-lysosomal proteins. The PHFs incorporated anionic molecules not observed in cell-derived PHFs, leading to a more compact filament fold. Multiple PHFs associated with one another and were linked to the luminal membrane at their ends. The PHF-containing EVs initiated propagation in directly-converted neurons, as well as in transgenic mice and a biosensor cell line. This work suggests that short PHFs are responsible for EV-mediated propagation of assembled tau in human brain. These results have broad implications for diagnostic and therapeutic strategies targeting extracellular assembled tau seeds in AD and other neurodegenerative diseases.

Project description:Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (stochastic version) Extension of a previously published stochastic model (designed to examine some of the key pathways involved in the aggregation of amyloid-beta (A β) and the micro-tubular binding protein tau ( BIOMD0000000286, BIOMD0000000462)) to include the main processes involved in passive and active immunisation against A β and then to demonstrate the effects of this intervention on soluble A β. This is the stochastic version of the model, the deterministic version is BIOMD0000000488. This model is described in the article: Investigating interventions in Alzheimer's disease with computer simulation models. Proctor CJ, Boche D, Gray DA, Nicoll JA. PLoS ONE 2013; 8(9): e73631 Abstract: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies. This model is hosted on BioModels Database and identified by: BIOMD0000000634. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (deterministic version) Extension of a previously published stochastic model (designed to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau ( BIOMD0000000286, BIOMD0000000462)) to include the main processes involved in passive and active immunisation against Aβ and then to demonstrate the effects of this intervention on soluble Aβ. This is the deterministic version of the model, the stochastic version is BIOMD0000000634. This model is described in the article: Investigating interventions in Alzheimer's disease with computer simulation models. Proctor CJ, Boche D, Gray DA, Nicoll JA. PLoS ONE 2013; 8(9): e73631 Abstract: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies. This model is hosted on BioModels Database and identified by: BIOMD0000000488. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.