The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

Buchholz, Sarah; Zempel, Hans

doi:10.1002/alz.13784

Cited by 5 publications

(5 citation statements)

References 453 publications

(860 reference statements)

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“…Due to the different accessibility of Aβ1-42 peptide regions within the fibril, we included peptide pools deriving from the linear Aβ1-42 divided into N-terminal, mid-sequence, and C-terminal pools ( Table S4 ). In addition, we included a peptide pool deriving from full-length 2N4R tau and axonal 0N4R tau variant representing both AD- and neurodegeneration-related antigens 54 . For the tau pool, we selected linear peptides showing higher predicted affinity towards HLA molecules using the NetMHCIIpan database 49,50 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer’s disease

Rickenbach,

Mallone,

Häusle

et al. 2024

Preprint

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There is growing evidence that the adaptive immune system and neurodegenerative Alzheimer’s disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing,in vitroT cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+T helper cell response towards β- amyloid peptide and display an early enrichment of cytotoxic CD8+effector/TEMRA cells in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI due to AD, we observed increased frequencies of CD8+effector/TEMRA cells in the periphery, characterized by a pro-inflammatory gene expression profile and an overall decrease in antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial in the preclinical stage to promote specific CD4+T cell responses, while in MCI it may be important to therapeutically target CD8+T cell responses if these prove to be harmful.

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Section: Resultsmentioning

confidence: 99%

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer’s disease

Rickenbach,

Mallone,

Häusle

et al. 2024

Preprint

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“…In this study, we aimed to identify domains or motifs of Tau and cellular interaction partners that are required for efficient axonal Tau sorting. Further, we wanted to unravel isoform-specific Tau interaction partners that might support the idea of different roles of human Tau isoforms in normal function and in disease development (Buchholz & Zempel, 2024).…”

Section: Discussionmentioning

confidence: 99%

“…The human Tau isoforms differ in their intracellular localization (Bachmann, Bell, et al, 2021; Buchholz et al, 2022; Zempel et al, 2017), and co-immunoprecipitation (Co-IP) experiments in rodent have revealed distinct binding partners suggesting isoform-specific roles in cellular Tau function (Liu et al, 2016). Comparable data are lacking for human Tau, although there is evidence for differential roles of human Tau isoforms in both health and disease (Buchholz & Zempel, 2024). Thus, we next looked for interaction partners that are specific for individual Tau isoforms, with the aim to find evidence for distinct functional roles in health and disease.…”

Section: Discussionmentioning

confidence: 99%

“…By rapid binding to or detaching from axonal MT filaments depending on its phosphorylation state (Biernat et al, 1993; Bramblett et al, 1993; Drechsel et al, 1992; Janning et al, 2014; Lindwall & Cole, 1984; Yoshida & Ihara, 1993), Tau controls the MT stability and is thus involved in axonal outgrowth, plasticity, cargo transport and other essential neuronal functions (Brandt et al, 1995; Caceres & Kosik, 1990; Dawson et al, 2010; Dixit et al, 2008; Drubin et al, 1985; Ebneth et al, 1998; Esmaeli-Azad et al, 1994; Hirokawa et al, 1988; Kempf et al, 1996; Liu et al, 1999; Samsonov et al, 2004; Takei et al, 2000; Trinczek et al, 1999). Notably, the Tau isoforms vary in their microtubule affinity and are thought to have distinct roles in Tau function and pathology (Bachmann, Bell, et al, 2021; Buchholz & Zempel, 2024; Bullmann et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Bell-Simons,

Buchholz,

Klimek

et al. 2024

Preprint

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Tau pathology is a major hallmark of Alzheimer’s disease (AD) and related diseases, called tauopathies. While Tau is normally enriched in axons, somatodendritic missorting of the microtubule-associated protein is a key event in early disease development. Tau missorting promotes synaptic loss and neuronal dysfunction but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. Interestingly, the disease-associated Tau brain isoforms show different axodendritic distribution, but the distinct role of these isoforms in health and disease largely unknown. Here, we aimed to identify domains or motifs of Tau and cellular binding partners that are required for efficient axonal Tau sorting, and we studied the differences of the isoform-specific Tau interactome. By using humanMAPT-KO induced pluripotent stem cell (iPSC)-derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncated or phosphorylation-mutant Tau constructs, and we used TurboID-based proximity labelling and proteomics to identify sorting- and isoform-specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N-terminal tail, the C-terminal repeat domains, and the general microtubule affinity of Tau. In contrast, the presence of the proline-rich region 2 (PRR2) was necessary for successful sorting. Our interactome data revealed peroxisomal accumulation of the Tau N-terminal half, while axonal Tau interacted with the PP2A activator HSP110. When we compared the interactome of 0N3R- and 0N4R-Tau, we observed specific interactions of 0N4R-Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, such as members of the CDC42 pathway and the RAB11 proteins, while 0N3R-Tau bound to MAP4 and other cytoskeletal elements. In sum, our study postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity, and unravels a potential isoform-specific role in synaptic function and AD-related dysfunction.

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“…The function and structure of tau are regulated by phosphorylation; however, in tauopathies including AD, FTD and DLB/PDD, tau proteins can become abnormally hyperphosphorylated. This hyperphosphorylation diminishes tau’s ability to bind to microtubules, leading to the formation of intracellular neurofibrillary tangles—one of the hallmarks neuropathologies of AD [166, 167].…”

Section: Future Directions and Limitationsmentioning

confidence: 99%

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Taha

2024

Preprint

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Accurate differential diagnosis of dementia disorders including Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and vascular cognitive impairment and dementia (VCID), along with conditions like prodromal mild cognitive impairment (MCI) or negative controls (NCs), continues to challenge neurologists. The nuanced and sometimes shared pathophysiological features underscore the need for precision in developing disease-modifying therapies. In the pursuit of reliable antemortem biomarkers, extracellular vesicles (EVs) have emerged as a popular tool for their capacity to encapsulate disease-specific signatures, particularly in neurodegenerative and neurological disorders. To this end, we have performed a comprehensive, PRISMA-guided systematic review and meta-analysis, utilizing sophisticated statistical modeling to determine the diagnostic accuracy, explore between-study variance and heterogeneity (I2), and investigate potential publication bias using various statistical tests.Biomarkers derived from general EVs demonstrated superior diagnostic accuracy, less between-study variance, heterogeneity, and publication bias than those from speculative CNS-enriched EVs. The trim-and-fill method suggested a potential overestimation of diagnostic effectiveness for biomarkers derived from CNS-enriched EVs due to four hypothesized missing studies with low diagnostic results, but none for general EVs. Meta-regressions revealed that studies using cerebrospinal fluid or serum, involving non-fasting individuals, sampling in the afternoon, employing citrate instead of EDTA for blood collection, using thrombin for coagulation factor depletion, isolating EVs with purer methods such as combined ultracentrifugation and size-exclusion chromatography, not freezing EVs post-isolation, and quantifying miRNA biomarkers, achieved better diagnostic accuracy and less heterogeneity. The diagnostic accuracy was low in differentiating among different dementia disorders. However, the analysis for diagnosing persons with AD vs. VCID achieved the highest diagnostic accuracy, suggesting that further studies may focus on this comparison. Additionally, we highlight several limitations in the included studies and recommend the following: Implement the use of appropriate negative controls, thorough documentation of preanalytical factors, inclusion of more dementia groups beyond AD, comprehensive reporting on pharmacological treatments, consideration of racial and ethnic minority groups, adherence to ISEV guidelines, application of the A-T-N framework, detailed documentation of dementia stages, extension of studies beyond differential diagnosis, reanalysis when postmortem definitive diagnostics become available, evaluation of prodromal conversion rates, and commitment to accurate statistical modeling and data transparency. We hope that lessons learned from this comprehensive meta-analysis can be beneficial for those attempting to discover biomarkers for AD and related dementias through EVs or alternative approaches.

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The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

Cited by 5 publications

References 453 publications

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer’s disease

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer’s disease

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

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