Staging of alzheimer's disease-related neurofibrillary changes

Braak, Heiko; Braak, Eva

doi:10.1016/0197-4580(95)00021-6

Cited by 2,077 publications

(1,666 citation statements)

References 34 publications

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“…We found that tauHMW was able to initiate tau aggregation in HEK TauRDP301S‐CFP/YFP cells (Holmes et al , 2014; Fig 5D), and, excitingly, showed rapid (1–2 min) phase separation into droplets as well as aggregation when applying crowding conditions (10% PEG, Fig 5E). Furthermore, by immunohistological labeling of phospho‐tau in post‐mortem human brain tissue with mild AD pathology (Braak stage III; Braak & Braak, 1995), we could find spherical phospho‐tau accumulations in hippocampal neurons (Fig EV6). These structures were apparent in neurons with aberrant mild accumulation of p‐tau in the cell body but not in neurofibrillary tangles with thioflavin‐S‐positive tau aggregates in the cell body; tau is normally excluded from the cell body and present only in the axon.…”

Section: Resultsmentioning

confidence: 91%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 91%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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“…This pathological misfolding of proteins in AD,4 ALS,5, 6 Parkinson's Disease (PD),7 and Huntington's Disease (HD) 8 suggests that an approach to inhibit the production of toxic proteins within the cell may be an effective therapy. One such approach includes lowering levels of RNA to decrease protein translation using molecules such as antisense oligonucleotides (ASOs) or small interfering RNA (siRNA).…”

Section: Introductionmentioning

confidence: 99%

Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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ObjectivesClinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA‐targeted therapies.MethodsTransgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule‐associated protein tau (hTau) or superoxide dismutase‐1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6‐leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics.Results ASO treatment lowered hTau mRNA and protein production (measured by 13C6‐leucine‐labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment.InterpretationMeasures of newly generated protein show earlier pharmacodynamics changes for RNA‐lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA‐targeted therapeutics.

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“…Numerous case studies and empirical investigations show that hippocampal damage can produce amnesic syndromes (Kramer & Delis, 1998). Alzheimer's disease (AD) is a particularly important target population to study because pathological signs of the disease are first observed in the medial temporal lobe, and memory impairment is a hallmark feature (Braak & Braak, 1995). Hippocampal atrophy in AD patients has been shown to predict impaired memory performance (Jack et al, 1999;Mungas et al, 2001;Petersen et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Hippocampal volume and retention in Alzheimer's disease

Kramer

Schuff

Reed

et al. 2004

J Int Neuropsychol Soc

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This study tested the hypothesis that the hippocampus has a relatively specific role in retaining information over delays. Thirty-seven subjects with probable Alzheimer's disease were evaluated with a verbal memory task and structural MRI. Cortical gray matter but not hippocampal volume predicted immediate free recall. In contrast, hippocampal volume was the best predictor of how well information was retained over a delay, even after controlling for levels of immediate recall. Results suggest that the role of the hippocampus is relatively specific to the consolidation of new memories.

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Staging of alzheimer's disease-related neurofibrillary changes

Cited by 2,077 publications

References 34 publications

Tau protein liquid–liquid phase separation can initiate tau aggregation

Tau protein liquid–liquid phase separation can initiate tau aggregation

Protein production is an early biomarker for RNA‐targeted therapies

Hippocampal volume and retention in Alzheimer's disease

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