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

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

Findings support a model in which tau dysfunction results from the convergence of molecular aberrations and genetic susceptibility within a pathological network involving amyloid-β, neuroinflammation, and synaptic failure.

Tau reduction counteracts transcriptomic and behavioral abnormalities in an Alzheimer amyloid model

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

It is reported that X-linked Dystonia-Parkinsonism (XDP), caused by a non-coding retrotransposon-associated repeat insertion in TAF1, involves a significant imbalance of tau isoforms and the accumulation of hyperphosphorylated, four-repeat tau in the brain.

Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease

Alzheimer’s disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated “pretangle” tau (pTau) in the locus coeruleus (LC), the brain’s primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the ‘LC-first’ phenomenon using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety-and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6, suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. Early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic characteristics. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying therapies to address neuropsychiatric manifestations.

A scalable human neuron model of Alzheimer’s disease relevant tauopathy reveals mechanisms linking Tau fibrillization to synaptic dysfunction

Tauopathies, including Alzheimer’s disease, are driven by pathological aggregation of hyperphosphorylated Tau, which disrupts synaptic integrity, impairs neuronal communication, and contributes to cognitive decline. To dissect tauopathy pathogenesis and enable therapeutic discovery, reliable and scalable human iPSC-neuron models are essential. Here, we developed two complementary iPSC-derived neuron models: an endogenous Tau seeding model, in which neurons are challenged with pre-formed Tau fragments that form paired helical filament (PHF)-consistent structures, and a Tau-0N3R overexpression seeding model to accelerate pathology. Both models recapitulate hallmark features of tauopathy, including the progressive formation of intracellular, hyperphosphorylated, sarkosyl-insoluble, and conformationally altered Tau aggregates (AT8, MC1 positive), along with synaptic and neuronal dysfunction. Cryogenic electron tomography (cryo-ET) further revealed the morphology of Tau fibrils within cells, as well as the ultrastructure of Tau fibrils trapping synaptic vesicles in situ. Using this platform, we performed integrated phosphoproteomics, high-content screening, and functional validation to identify key pathways driving Tau aggregation. MARK2-mediated phosphorylation within Tau’s microtubule-binding domain emerged as an early trigger of aggregation, confirmed by site-specific mutagenesis. In parallel, small molecules targeting the PI3K/mTOR/GSK3 pathway reduced aggregation and restored synaptic function, with GSK3 inhibition lowering phosphorylation at critical aggregation-driving sites on Tau. Together, these findings establish a physiologically relevant, scalable platform for therapeutic screening that connects Tau seed uptake, site-specific phosphorylation, fibril formation, and synaptic disruption, ultimately identifying mechanistically separable intervention points along the aggregation cascade. HIGHLIGHTS - Development of scalable iPSC-neuron models enables tauopathy drug discovery and reconstructs progressive Tau seeding, fibrillization and synaptic dysfunction - Cryo-ET reveals the ultrastructure of Tau fibrils within human neurons and their accumulation at synapses. - Temporal phosphoproteomics identifies early modulation of MARK-regulated Tau phosphosites. - PI3K–mTOR and GSK3 regulate distinct stages of the Tau aggregation cascade. - Site-specific mutagenesis confirms critical Tau residues required for Tau aggregation.

Neuron-specific suppression of aberrantly active Toll-NFκB signalling mitigates pathogenic tau hyperphosphorylation via Gsk-3β in Drosophila.

Chronic brain ailments like Alzheimer's disease and Frontotemporal dementia, together referred to as tauopathies, are strongly influenced by neuroinflammation, an age-associated functional anomaly. Neuroinflammation arising from a dysfunctional innate immune response, such as Toll-NFκB signalling, is implicated in modulating tau pathophysiology, with limited understanding of the molecular mechanisms. Pathogenic hyperphosphorylation of tau and its aggregation into neurotoxic species is considered as a central trigger of tau pathology; however, the mechanistic association between these pathogenic events and the Toll signalling remains largely unexplored. We examined the status of the Toll signalling in Drosophila tauopathy models and evaluated whether its modulation modifies disease severity. We present compelling evidence that neuronal expression of pathogenic human tau causes aberrant activation of the Toll signalling. In line, its additional upregulation further aggravates disease severity, while genetic downregulation of Toll components remarkably alleviates both structural and functional deficits. We subsequently noted that knockdown of the Toll pathway attenuates pathogenic tau hyperphosphorylation in a site-specific manner, largely coinciding with restoration of physiological activity of Gsk-3β/Akt/PP2Ac signalling, a relatively less explored molecular axis in neurons. Our study posits a potential contribution of neuron-intrinsic altered Toll signalling cascade in tau pathogenesis, warranting further exploration of this evolutionarily conserved pathway as a therapeutic target.