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Tau filaments from the cellular fraction of Alzheimer's disease patient brain

ABSTRACT:

SUBMITTER: Benjamin Ryskeldi-Falcon

PROVIDER: EMPIAR-11318 | biostudies-other |

REPOSITORIES: biostudies-other

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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:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.