Tau-targeting therapies for Alzheimer disease: current status and future directions

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(12), P. 715 - 736

Published: Oct. 24, 2023

Language: Английский

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Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

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

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Trem2 deletion enhances tau dispersion and pathology through microglia exosomes

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 2, 2022

Alzheimer's disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated enhanced risk of onset sporadic (AD). While recent studies suggest dysfunction can aggravate pathology, mechanisms underlying TREM2-dependent modulation remains elusive.Here, we characterized differences progressive spreading from medial entorhinal cortex (MEC) to hippocampus wildtype (WT) Trem2 knockout (KO) mice by injection AAV-P301L into MEC, correlated changes hippocampal histopathology spatial fear memory. We also compared effects intraneuronal dispersion between cultured microglia neurons using microfluidic assay, analyzed trafficking following uptake, quantified exosomal secretion pathogenicity purified WT KO exosomes.Trem2 deletion (Trem2 KO) enhance hippocampus, which coincides impaired synaptic function memory behavior. enhances vitro neuronal layers chamber, presence exosome inhibitors significantly reduce exosomes extracellular media tau-loaded microglia. Although has no effect on distribution endosomal cellular pre-exosomal compartments internalization. little size, however, proteomic analysis indicates modulate landscape LPS/ATP treatment conditions induction. Furthermore, show elevated levels, feature tau-seeding capacity FRET reporter line microglia.Together, our results reveal role for suppressing pathogenicity, demonstrates trafficking, seeding through exosomes.

Language: Английский

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Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(5), P. 351 - 371

Published: April 4, 2024

Language: Английский

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Disentangling tau: One protein, many therapeutic approaches

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(2), P. e00321 - e00321

Published: Jan. 25, 2024

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy collectively impact millions patients their families worldwide. Despite years drug development using a variety mechanisms action, no therapeutic directed against has been approved for clinical use. This raises important questions about our current model pathology invites thoughtful consideration approach to nonclinical models trial design. In this article, we review what is known biology genetics tau, placing it in context failed trials. We highlight potential reasons lack success date offer suggestions new pathways development. Overall, viewpoint future optimistic group diseases.

Language: Английский

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Current Progress and Future Directions in Non-Alzheimer’s Disease Tau PET Tracers

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(2), P. 111 - 127

Published: Jan. 6, 2025

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [18F]FDDNP, [11C]PBB3, [18F]flortaucipir, [18F]THK series, for vivo detection has marked a significant breakthrough fields neuroscience radiopharmaceuticals, creating robust new category labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other PET tracers with improved binding properties have been developed using various chemical scaffolds to target three-repeat/four-repeat (3R/4R) folds AD. In 2020, [18F]flortaucipir was approved U.S. Food Drug Administration imaging pathology adult patients cognitive deficits undergoing evaluation Despite remarkable progress development AD tracers, agents rare (4R [predominantly expressing 4R isoform], involved progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, 3R such as Pick's disease) remain substantially underdeveloped. this review, we discuss recent tracer development, particular emphasis on clinically validated their potential use tauopathies. Additionally, highlight critical need further specifically designed tauopathies, an area that remains significantly underexplored despite its importance advancing understanding diagnosis these disorders.

Language: Английский

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Classification of diseases with accumulation of Tau protein

Neuropathology and Applied Neurobiology, Journal Year: 2022, Volume and Issue: 48(3)

Published: Jan. 22, 2022

Abnormal filaments of known composition in neurons and glia define many sporadic hereditary human neurodegenerative diseases. The pathogenic significance filamentous inclusions became evident when cases dominantly inherited disease were shown to be associated with mutations the genes encoding proteins that make up filaments, they Tau [1-3], Aβ [4, 5], α-synuclein [6], prion protein [7], TDP-43 [8-10] or FUS [11, 12]. By extrapolation, it follows a gain-of-toxic function resulting from ordered assembly into may also underlie forms disease. Assemblies microtubule-associated characterise In humans, MAPT, gene protein, generates six isoforms (352–441 amino acids) by alternative mRNA splicing [13]. They differ presence absence three inserts encoded exons 2, 3 10. Inclusion exon 10 results production four C-terminal repeats (each repeat is 31 32 acids long) (4R) its exclusion another (3R). Diseases characterised intracellular accumulation can divided groups, based on isoform (3R, 4R, 3R + 4R) [14]. these diseases, inherited, extensively modified post-translationally [15-17]. Tauopathy was coined describe +3 mutation intron MAPT abundant made 4R [3, 18]. However, this term used neuropathology neuroscience refer mere tissues. terms primary secondary tauopathies are being [19-25], even though only aetiology for Tauopathies. Primary tauopathy refers conditions where main sole abnormality tau pathology considered major contributing factor neurodegeneration interpreted as 'driving force pathogenesis', opposed other such [23, 25-28]. included group frontotemporal lobar degeneration (FTLD). latter predominant atrophy frontal temporal lobes cerebral cortex occurs association several different proteinopathies [29]. Secondary additional forces' believed involved [19]. our view, example tauopathy, whereas familial Alzheimer's tauopathy. These should not referring diseases unknown aetiology. pathologic classified basis isoforms, 3R, both demonstrable isoform-specific antibodies Western blot patterns sarkosyl-insoluble Tau. anatomical distribution, along histological cytological characterisation neuronal glial immunoreactivities, needed clinicopathological classification [19, 20, 30]. Formation abnormal central event Like amyloids, have cross-β conformation [31]. Recently, folds [32, 33], Pick's [34], chronic traumatic encephalopathy (CTE) [35], corticobasal (CBD) [36, 37], argyrophilic grain (AGD), progressive supranuclear palsy (PSP) globular (GGT) [38] different. filament fold age-related (PART) identical Alzheimer fold, indicating form deposits [39]. same structures been found individuals given It noteworthy those coexisted parenchymal amyloid, PrP Abri ADan amyloid [38, 40]. brains carriers AGD. Structural analysis has led discovery potentially new entities [38]. now timely update existing terminology re-examine grouping disorders accumulation, because (1) there an increased interest role neurodegeneration, (2) inconsistent (3) high-resolution determined. Here, we put forward definitions various conditions, well simple flexible stratification system will allow inclusion novel pathological entities. Identification brain provided compelling argument reconsidering nomenclature organisation which play role. Because 'tauopathy' rigorously defined, need establish precise meaning, so avoid use. This implies assembled through interpretation obtained using at least one following: silver staining, immunohistochemistry, immunofluorescence, electron microscopy, immunoblotting seeding. describes lesions, definition acknowledges each condition spectrum regional load (i.e. stages sequential involvement regions), thus implying early recognisable disorder. Therefore, described pathology. summary, cellular immunoreactivities 'Tau immunoreactivity' neurons, astrocytes, oligodendrocytes, etc.; pathology', but 'Tauopathy', lesions revealed routine diagnostic immunohistochemistry; 'Tauopathy' until consistent staining pattern demonstrated We propose following approach categorising immunoreactivity relevance groups. requires knowledge aetiology, if known, Tau-only vs coexistence than pathogenesis. Each then subdivided according involved, immunostaining and/or well-characterised Tau-specific antibodies. knowledge, say 'awaiting classification'. defined specific morphological changes, their phenotypes historically assigned names. Finally, cryo-EM folds, Tauopathies further Our still evolving, lead identification previously unrecognised conditions. Rather divide Tauopathies, classify five groups (Table 1). Group 1 includes MAPT. Some similar 43]. 2 pivotal neuropathological diagnosis correlate clinical symptoms Nomenclature either presentation PSP), distribution CBD), morphology pathologies GGT AGD) eponyms disease). Groups summarised 'main tauopathies' (Figure extracellular (Aβ, Bri). 4 idiopathic 'extracellular deposit-related 5 comprises show overlapping features 3. reported less frequently 6 some cases, described, demonstrated. observed who clinically normal, represent preclinical stage cytopathological phase fibril formation [27]. recommend pathology' rather detected, constitute obstacle more characterisation: cytopathology inconsistently detected between belonging conditions; single case reports; related unclear. Moreover, include neurofibrillary tangles anatomically circumscribed areas often unrelated leading constellations reports compatible 1–5. proposed Figure 1. Tauopathy-like diverse aetiologies 2). present without Tauopathy, direct relation disorder Young-onset Late-onset Neuro-astroglial variants elderly [46-48] hippocampal 4-repeat immunoreactive spherical [49-51] limbic-predominant body (LNT) Diffuse NFTs calcification (Kosaka-Shibayama [52] Pacific ALS/PDC (Guam, Kii Peninsula) [53-56] Nodding syndrome-related [57]aa Conditional, future studies. Chronic IgLON5 antibody-related [58]aa Post-encephalitic parkinsonism [59]aa Familial behavioural variant dementia astrocyte-predominant [60, 61] Vacuolar autosomal-dominant VCP hypomorph (D395G) [62] Niemann–Pick type C-related [63-66]aa Progressive ataxia palatal tremor-related (one study immunostaining, no biochemistry) [67, 68] Subacute sclerosing panencephalitis-related [69-73]aa Ganglioglioma [110] Meningioangiomatosis [111-113] Hemimegalencephaly [114] Tuberous sclerosis complex [115] Focal cortical dysplasia Huntington's disease: reduction soluble increase phosphorylation epitopes, monomers; upregulation 4R-Tau levels; 4R:3R ratio weaker bands [85, 118, 119] PART/AD, AGD PSP-like multiple Lewy AGD, PSP, CBD, AD degeneration/motor neuron proteinopathy ARTAG, PSP AGD-like Creutzfeldt–Jakob variably protease-sensitive prionopathy [84, 122] ARTAG [123] cerebrotendinous xanthomatosis [124] DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability seizures) syndrome [125] myotonic dystrophy [126] asymptomatic I carrier individual mental retardation [127] AD-like LRRK2 [128, 129] PRKN [130] PART/AD genetic 92] AD/PART-like C9ORF72, GRN SNCA [131-137] AD, CTE PART-like [138-140] benign chorea mapped chromosome 8q 21.3-q23.3 [141] Pick PSEN1 [142, 143] C9ORF72 A239T [144] AD- spinocerebellar [145] As consequence developments understanding generated, widely used. involving non-Tau proteinopathies, genetics accumulated experience correlations, complemented structures. easily accommodate discoveries moved groups). hopefully working communicate findings concise unambiguous ways inform therapeutic developments. GGK supported Rossy Foundation Edmond Safra Philanthropic Foundation. MG UK Medical Research Council (MC_U105184291). BG NIH grants (U01 NS110437 RF1 AG071177-01A1). authors report conflicts manuscript. GGK, BG, all contributed design conception paper wrote peer review history article available https://publons.com/publon/10.1111/nan.12792.

Language: Английский

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LRP1 is a neuronal receptor for α-synuclein uptake and spread

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 2, 2022

The aggregation and spread of α-synuclein (α-Syn) protein related neuronal toxicity are the key pathological features Parkinson's disease (PD) Lewy body dementia (LBD). Studies have shown that species α-Syn tau can in a prion-like manner between neurons, although these two proteins distinct roles contribute to different neurodegenerative diseases. It is reported low-density lipoprotein receptor-related 1 (LRP1) regulates proteins; however, molecular regulatory mechanisms uptake spread, whether it also regulated by LRP1, remain poorly understood.We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using CRISPR/Cas9 strategy generated iPSC-derived neurons (iPSNs) test role uptake. We treated iPSNs with fluorescently labeled measured internalization flow cytometry. Three forms were tested: monomers, oligomers, pre-formed fibrils (PFFs). To examine lysine residues involved LRP1-mediated uptake, we capped amines lysines on sulfo-NHS acetate then internalization. tested N-terminus critical for Lastly, investigated Lrp1 regulating conditional (Lrp1-nKO) mouse model. adeno-associated viruses (AAVs) allowed distinguishing expression versus injected them into hippocampus six-month-old Lrp1-nKO mice littermate wild type (WT) controls. was evaluated three months after injection.We found both monomeric oligomeric significantly reduced LRP1-KO compared WT PFFs inhibited iPSNs, albeit much lesser extent monomers oligomers. blocking effectively decreased Finally, mice, littermates.We identified as regulator well an important mediator brain. This study provides new knowledge physiological trafficking pathology, offering insight treatment synucleinopathies.

Language: Английский

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Tau interactome and RNA binding proteins in neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Oct. 17, 2022

Pathological tau aggregation is a primary neuropathological feature of many neurodegenerative diseases. Intriguingly, despite the common presence aggregates in these diseases affected brain regions, clinical symptoms, and morphology, conformation, isoform ratio present varies widely. The tau-mediated disease mechanisms that drive are still unknown. Tau interactome studies critically important for understanding tauopathy. They reveal interacting partners define pathways, interactions provide potential insight into cellular environment protein during pathological aggregation. Here we combined analysis 12 human tissue, cell culture models rodent disease. Together, identified 2084 proteins interact with tissue 1152 Our revealed consistent enrichment between involved RNA binding, ribosome, proteasome function. Comparison substantial differences two species. We also performed second to identify enriched neurons containing granulovacuolar degeneration or neurofibrillary tangle pathology. These results timed dysregulation as pathology develops. binding proteins, particularly HNRNPs, emerged early disease-associated interactors therefore may have an role driving

Language: Английский

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Tau Isoforms: Gaining Insight into MAPT Alternative Splicing

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 15383 - 15383

Published: Dec. 6, 2022

Tau microtubule-associated proteins, encoded by the MAPT gene, are mainly expressed in neurons participating axonal transport and synaptic plasticity. Six major isoforms differentially during cell development differentiation translated alternative splicing of transcripts. Alterations expression human their aggregation have been linked to several neurodegenerative diseases called tauopathies, including Alzheimer's disease, progressive supranuclear palsy, Pick's frontotemporal dementia with parkinsonism chromosome 17. Great efforts dedicated recent years shed light on complex regulatory mechanism splicing, a perspective developing new RNA-based therapies. This review summarizes most contributions knowledge isoform experimental models, highlighting role cis-elements ribonucleoproteins that regulate exons.

Language: Английский

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