Tau isoform imbalance and aggregation are pathological hallmarks of X-linked dystonia-parkinsonism

The molecular and genetic view of tauopathies: From structural polymorphism to systemic neurodegeneration

Tauopathies constitute a broad group of clinically heterogeneous neurodegenerative disorders, including Alzheimer’s disease, progressive supranuclear palsy, and Pick’s disease, characterized by abnormal metabolism, misfolding, and intracellular aggregation of the microtubule-associated protein tau. These diseases are defined by disruptions in alternative splicing of the tau protein, toxic post-translational modifications such as hyperphosphorylation and acetylation, and the “prion-like” spread of pathological tau seeds across anatomically connected regions. Recent cryogenic electron microscopy studies have demonstrated that each tauopathy has a unique filament-folding structure, elucidating the molecular basis of phenotypic variation among diseases. The aim of this review is to provide a holistic perspective by synthesizing recent developments in the molecular and genetic architecture of tauopathies, particularly newly discovered genetic risk loci and cellular proteostasis mechanisms. In this context, detailing the process from the physiological functions of the tau protein to its pathological transformation aims to analytically evaluate the diagnostic value of fluid biomarkers and current data on next-generation clinical-stage therapeutic strategies, such as monoclonal antibodies and antisense oligonucleotides.

MAPT-derived circTau6 induces tau pathogenesis and neurodegeneration by encoding Tau variants.

PIAS1-mediated GSK3β SUMOylation exacerbates tauopathy and cognitive deficits in Alzheimer's disease models.

A conserved serotonin receptor pathway is a druggable modifier of Tau pathology, neural circuit formation and neurodegeneration

Background Tauopathies are devastating neurodegenerative disorders characterized by Tau hyperphosphorylation, neurofibrillary tangle (NFT) formation, neuronal dysfunction, and cognitive decline. Methods Here, we establish a new Drosophila tauopathy model expressing eGFP-tagged human TauWT or the disease-associated TauP301L variant in the nervous system. Results TauP301L expression recapitulates key pathological and behavioral hallmarks of tauopathy, including elevated Tau hyperphosphorylation, accumulation of NFT-like, pTau-positive assemblies in vivo, reduced lifespan, hyperactivity, sleep loss, progressive locomotor decline, and age-dependent brain degeneration. Strikingly, TauP301L also disrupts the architecture of the mushroom body, a learning- and memory-related circuit in Drosophila, revealing an early disruption of neural circuit formation that is distinct from adult neurodegenerative phenotypes. We further show that suppression of serotonin 5-HT7R-CDK5 signaling pathway, either by genetic knockdown or pharmacological inhibition with inverse agonist, rescues Tau-induced behavioral and anatomical phenotypes. Conclusions These findings identify 5-HT7R signaling as a conserved and druggable modifier of Tau toxicity and establish this model as a powerful in vivo platform for mechanistic studies and therapeutic discovery in tauopathies.

Tau dysfunction in alzheimer’s disease: molecular and cellular mechanisms, genetic modulation, and therapeutic perspectives

GWAS of Tau‐Neurodegeneration Mismatch Identifies New Risk Loci for Susceptibility to Tau

ABSTRACT Background In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau‐neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. Methods Here, I perform a genome‐wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. Results A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome‐wide significance threshold (p ≤ 5 × 10−8). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10−8; rs9784993, MAF = 0.197, p = 4.92 × 10−8) was associated with lower Tau/Neurodegeneration residuals, indicating higher‐than‐expected neurodegeneration given tau levels. Conclusion GWAS of tau‐related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau‐neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.