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.
Alzheimer's disease (AD) is the most dominant form of dementia characterized by neurodegeneration which leads to progressive cognitive decline and memory loss, the common symptoms of AD. While amyloid-β peptide accumulation has traditionally been the primary focus of AD research, there is growing evidence that tau pathology also contributes significantly in disease progression. Tau is a microtubule-associated protein that normally stabilizes microtubules and supports axonal transport within neurons. However, abnormal hyperphosphorylation causes tau to detach from microtubules, misfold and aggregate into toxic filaments which ultimately lead to neurodegeneration and eventually cell death. This paper reviews the structure of tau protein, its physiological and pathological behaviours and tau's mechanism in terms of disease progression. This paper also examines clinical and preclinical evidences and discusses the efficacy and limitations of three tau-targeted therapeutic approaches: gosuranemab, a monoclonal antibody designed to prevent the spread of extracellular tau; BIIB080, an antisense oligonucleotide that reduces tau production by targeting MAPT mRNA; and leucomethylthioninium bis (LMTM), a tau aggregation inhibitor. Studies also suggest the potential of combination therapies targeting multiple pathological pathways to enhance efficacy. Though no tau-targeted therapy has yet to demonstrate definitive clinical benefit, continued research supports tau as an important therapeutic target and contributes to the development of more effective treatments for AD.
A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.
Lian-Jing Xu, Ying Zhang, Li Jiang et al.· Frontiers in Cellular Neuros...· 0 citations
The current understanding of the genetic and physiological mechanisms underlying Alzheimer’s disease is reviewed and modern approaches for diagnosis and treatment are discussed.
Zahraa Mohammed Fakheir, S. A. H. Jasim· Journal of Genetic and Envir...· 0 citations
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.
J. Lipka, Xiwei Shan, Qiao Zhang et al.· bioRxiv· 0 citations
While amyloid-β (Aβ) has historically dominated the research landscape of Alzheimer’s disease (AD), the limited clinical success of Aβ-centric therapies has redirected focus toward tau pathology, which correlates more robustly with cognitive deterioration and synaptic dysfunction. Transcending the traditional linear pathological model, this review reframes tau phosphorylation as a dynamic hub within a multi-scale regulatory network. We first synthesize recent breakthroughs in molecular mechanisms, detailing how the kinase-phosphatase equilibrium, cross-regulation of diverse post-translational modifications (PTMs), nuclear envelope damage, iron metabolism and ferroptosis collectively drive the transition from soluble tau species to neurofibrillary tangles (NFTs). Beyond neuronal boundaries, we elucidate how pathological tau orchestrates systemic neurotoxicity by synergizing with Aβ deposition to trigger neuroinflammation, blood-brain barrier breakdown, and gut-brain axis dysregulation. Finally, we bridge these mechanistic insights with translational advancements, evaluating next-generation biofluid biomarkers and innovative therapeutic modalities—ranging from small-molecule inhibitors to Dephosphorylation-Targeting Chimeras (DEPTACs)—currently under clinical investigation. This integrated perspective offers a holistic framework for understanding AD pathogenesis and provides a roadmap for the development of precision medicine strategies targeting the tau interactome.
Xue Li, Lei-Han Zhang, Li-Jun Zhao et al.· Journal of Translational Med...· 0 citations
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, pathologically defined by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The Braak staging system established that tau pathology spreads in a stereotypical pattern across the brain, supporting the “prion-like” hypothesis: misfolded tau aggregates serve as seeds, inducing the misfolding and aggregation of normal tau, and thereby driving disease progression along neuroanatomical pathways. In the past 5 years (2021–2026), substantial advances have elucidated the molecular mechanisms underlying tau seeding activity. This review summarizes recent progress in tau seeding research, highlighting both intrinsic and extrinsic regulators of tau prion-like activity. Intrinsic factors include the structural basis of tau strains, MAPT mutations, alternative splicing (3R/4R isoforms), post-translational modifications, and liquid–liquid phase separation. Extrinsic factors encompass cofactors, molecular chaperones, non-coding RNAs, epigenetic mechanisms, environmental exposures, and the emerging concept of trans-seeding by heterologous protein fibrils. We also review therapeutic strategies targeting tau pathology, focusing on their mechanisms and clinical development. Integrating these mechanistic insights and therapeutic advances will inform future research and clinical strategies for AD and related tauopathies.
Jin Miao, Chun-Hong Xue, Xu Yan et al.· Frontiers in Neuroscience· 0 citations
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