CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis DOI Creative Commons

Avi J. Samelson,

Nabeela Ariqat, Justin McKetney

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 17, 2023

Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to aggregation subsequent dysfunction death, but underlying mechanisms unknown. To systematically uncover cellular factors controlling accumulation aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen iPSC-derived neurons. The uncovered expected pathways, including autophagy, also unexpected UFMylation GPI anchor synthesis. We discover that E3 ubiquitin ligase CUL5

Language: Английский

PROTAC targeted protein degraders: the past is prologue DOI Open Access
Miklós Békés, David R. Langley, Craig M. Crews

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(3), P. 181 - 200

Published: Jan. 18, 2022

Language: Английский

Citations

1926
Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials DOI
Rik Ossenkoppele, Rik van der Kant, Oskar Hansson

et al.

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 21(8), P. 726 - 734

Published: May 25, 2022

Language: Английский

Citations

295
Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration DOI Creative Commons
Tara E. Tracy, Jesús Madero‐Pérez, Danielle L. Swaney

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(4), P. 712 - 728.e14

Published: Jan. 20, 2022

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize interactomes modified activity mutations that cause frontotemporal dementia (FTD) human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of presynaptic vesicle proteins during activity-dependent secretion mapped Tau-binding sites cytosolic domains integral synaptic proteins. showed FTD impair bioenergetics markedly diminished Tau's interaction mitochondria proteins, which were downregulated AD brains multiple cohorts correlated severity. These multimodal dynamic exquisite spatial resolution shed light on role function highlight potential therapeutic targets block Tau-mediated pathogenesis.

Language: Английский

Citations

219
GSK-3 and Tau: A Key Duet in Alzheimer’s Disease DOI Creative Commons
Carmen Laura Sayas, Jesús Ávila

Cells, Journal Year: 2021, Volume and Issue: 10(4), P. 721 - 721

Published: March 24, 2021

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with plethora of substrates. As modulator several cellular processes, GSK-3 has central position in cell metabolism and signaling, important roles both physiological pathological conditions. been associated number human disorders, such as neurodegenerative diseases including Alzheimer's disease (AD). contributes to the hyperphosphorylation tau protein, main component neurofibrillary tangles (NFTs), one hallmarks AD. further involved regulation different neuronal processes that are dysregulated during AD pathogenesis, generation amyloid-β (Aβ) peptide or Aβ-induced death, axonal transport, cholinergic function, adult neurogenesis synaptic function. In this review, we will summarize recent data about involvement these contributing pathology, mostly focusing on crucial interplay between protein. We discuss current development potential therapies targeting GSK-3-phosphorylated tau.

Language: Английский

Citations

203
Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms DOI
Nicole Koutsodendris, Maxine Nelson,

Antara T. Rao

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2021, Volume and Issue: 17(1), P. 73 - 99

Published: Aug. 30, 2021

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It notoriously difficult to develop therapeutics for AD due its complex nature. Nevertheless, recent advancements in imaging technology the development innovative experimental techniques have allowed researchers perform in-depth analyses uncover pathogenic mechanisms AD. An important consideration when studying late-onset major genetic risk factor, apolipoprotein E4 (apoE4). Although exact underlying apoE4 effects on initiation progression are not fully understood, studies revealed critical insights into apoE4-induced deficits occur In this review, we highlight notable detail prominent pathologies, including amyloid-β, tau pathology, neuroinflammation, neural network dysfunction. We also discuss evidence defines physiological functions apoE outlines how these disrupted apoE4-related

Language: Английский

Citations

166
Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro DOI Creative Commons
Paul M. Seidler, Kevin A. Murray, David R. Boyer

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 16, 2022

Abstract Alzheimer’s disease (AD) is the consequence of neuronal death and brain atrophy associated with aggregation protein tau into fibrils. Thus disaggregation fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known disaggregate other amyloid fibrils, but EGCG poor drug-like properties, failing fully penetrate brain. Here we have cryogenically trapped an intermediate brain-extracted on kinetic pathway EGCG-induced determined its cryoEM structure. structure reveals that molecules stack polar clefts between paired helical protofilaments pathologically define Treating binding position as pharmacophore, computationally screened thousands compounds for compatibility discovering several experimentally brain-derived vitro. This work suggests potential structure-based, small-molecule drug discovery diseases.

Language: Английский

Citations

128
Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies DOI Creative Commons
Galina Limorenko, Hilal A. Lashuel

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 51(2), P. 513 - 565

Published: Dec. 10, 2021

We discuss novel approaches for embracing and reproducing complexity of Tau pathology required developing disease-relevant diagnostics effective therapies.

Language: Английский

Citations

118
Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease DOI Creative Commons
Edmond Teng, Paul T. Manser,

Karen Pickthorn

et al.

JAMA Neurology, Journal Year: 2022, Volume and Issue: 79(8), P. 758 - 758

Published: June 13, 2022

Importance

Neurofibrillary tangles composed of aggregated tau protein are one the neuropathological hallmarks Alzheimer disease (AD) and correlate with clinical severity. Monoclonal antibodies targeting may have potential to ameliorate AD progression by slowing or stopping spread and/or accumulation pathological tau.

Objective

To evaluate safety efficacy monoclonal anti-tau antibody semorinemab in prodromal mild AD.

Design, Setting, Participants

This phase 2 randomized, double-blind, placebo-controlled, parallel-group trial was conducted between October 18, 2017, July 16, 2020, at 97 sites North America, Europe, Australia. Individuals aged 50 80 years (inclusive) AD, Mini-Mental State Examination scores 20 30 (inclusive), confirmed β-amyloid pathology (by positron emission tomography cerebrospinal fluid) were included.

Interventions

During 73-week blinded study period, participants received intravenous infusions placebo (1500 mg, 4500 8100 mg) every weeks for first 3 4 thereafter.

Main Outcomes Measures

The primary outcomes change from baseline on Clinical Dementia Rating–Sum Boxes score week 73 assessments tolerability compared placebo.

Results

In modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases seen 126; Δ 2.19 [95% CI, 1.74-2.63]) mg: n 86; 2.36 1.83-2.89]; 1.92-2.79]; 84; 2.41 1.88-2.94]) arms. safety-evaluable 441), proportions experienced adverse events (130 [93.1%]) 89 [88.8%]; 132 [94.7%]; 90 [92.2%])

Conclusions Relevance

this randomized trial, did not slow throughout period but demonstrate an acceptable well-tolerated profile. Additional studies be needed determine utility therapeutic approach.

Trial Registration

ClinicalTrials.gov Identifier:NCT03289143

Language: Английский

Citations

115
Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials DOI Creative Commons
Adam L. Boxer, Reisa A. Sperling

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4757 - 4772

Published: Oct. 1, 2023

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as selection patients at relatively early stages disease. Biomarkers target pathologies, including tau PET, insights from past were also critical successes. Moving forward, challenge will be develop more efficacious greater efficiency. Novel trial designs, combination umbrella basket protocols, accelerate development. Better diversity inclusivity participants are needed, blood-based biomarkers may help improve access medically underserved groups. Incentivizing innovation in both academia industry through public-private partnerships, collaborative mechanisms, creation career paths build momentum exciting times.

Language: Английский

Citations

89
The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis DOI Creative Commons

Francesca R. Buccellato,

Marianna D’Anca, María Serpente

et al.

Biomedicines, Journal Year: 2022, Volume and Issue: 10(9), P. 2261 - 2261

Published: Sept. 13, 2022

Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson's (PD) a movement disorder. These two disorders share accumulation toxic proteins as pathological hallmark. The lack definitive disease-modifying treatments for these neurogenerative diseases has led to hypothesis new pathogenic mechanisms target and design potential therapeutic approaches. recent observation that glymphatic system supposed be responsible cerebrospinal fluid into brain clearance metabolic waste study its involvement in pathogenesis classic proteinopathies. Aquaporin-4 (AQP4), water channel located endfeet astrocyte membrane, considered primary driver system, defective AQP4-mediated drainage been linked objective present review body knowledge links AD PD other lifestyle factors such sleep deprivation exercise may influence function. We will also focus on neuroimaging approaches could identify marker detect changes.

Language: Английский

Citations

83