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INTRODUCTION Misfolded tau can assemble into oligomers that adopt distinct conformations, referred to as polymorphs, each with unique biochemical and pathological properties. These tau polymorphs are thought to influence disease progression in Alzheimer's disease (AD) and related disorders. Interestingly, some individuals with AD pathology remain cognitively intact (non‐demented with Alzheimer's neuropathology [NDAN]), suggesting potential differences in tau polymorph profiles. METHODS Brain‐derived tau oligomers (BDTOs) were isolated from post mortem hippocampi of AD and NDAN individuals. Their biophysical, biochemical, and functional properties were assessed via protease digestion, immunocharacterization, atomic force microscopy, tau seeding in biosensor cells, hippocampal slice electrophysiology, and SH‐SY5Y toxicity assays. RESULTS NDAN‐BDTOs exhibited protease resistance, different conformational profiles, formed larger aggregates, preserved synaptic function, and reduced neuronal toxicity compared to AD‐BDTOs. DISCUSSION The data suggests that a structurally stable yet less toxic tau polymorph in NDAN may underlie cognitive resilience, supporting the therapeutic relevance of targeting specific tau polymorphs. Highlights Non‐demented with Alzheimer's neuropathology (NDAN) brain‐derived tau oligomers (BDTOs) exhibit distinct, more stable structural polymorphs compared to those from Alzheimer's disease (AD). NDAN‐BDTOs are larger, more protease resistant, and less toxic in cell and hippocampal slice models. Both NDAN‐ and AD‐BDTOs seed tau aggregation, but NDAN‐BDTOs promote formation of less toxic assemblies. Structural stability of NDAN‐BDTOs may contribute to cognitive resilience despite AD pathology. Mimicking non‐toxic tau polymorphs could represent a novel therapeutic strategy for AD.

Tau oligomers are recognized for their critical role in causing neuronal toxicity and synaptic dysfunction in a diverse array of neurodegenerative diseases collectively referred to as tauopathies. However, the discovery of drugs that specifically target tau oligomers has been impeded by the absence of appropriate screening methods. Here, we suggest a drug screening platform based on tau amyloid corona‐shelled nanoparticles (TACONs) to assess the efficacy of tau oligomer‐degrading agents through aggregation‐induced colorimetric responses of TACONs. TACONs were engineered via the encapsulation of gold nanoparticles (AuNPs) with homogeneous tau oligomers by leveraging heparin as a co‐factor. Our TACON‐based strategy harnesses two primary functions of AuNPs: (i) catalytic activators for the selective isolation of tau oligomers and (ii) optical reporters for quantifying colorimetric responses induced by tau oligomer‐degrading agents. To validate this approach, we employed proteases that can degrade tau oligomers (protease XIV and plasmin) along with various small molecules known to aid in the treatment of tauopathies. Furthermore, we significantly enhanced screening efficiency by integrating a time‐series deep learning architecture, enabling rapid identification of effective agents within 1 h. These results highlight the great potential of a deep learning‐assisted TACON‐based drug screening platform as a powerful strategy for streamlining drug discovery in tauopathies. Tau amyloid corona‐shelled nanoparticles (TACONs) were synthesized by incubating gold nanoparticles (AuNPs) with tau monomers that had been pre‐reacted with heparin. These TACONs represent a promising high‐throughput screening platform for identifying tau oligomer degraders as potential therapeutic agents for Alzheimer's disease. Furthermore, the integration of artificial intelligence (AI) technology into the screening process can significantly reduce screening time.

The cell-to-cell transmission of tau aggregates is considered a mechanism underlying the intracerebral spreading of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Recent studies suggest that tau oligomers, rather than fibrils, participate in this process. We previously showed that intranasal rifampicin inhibits tau oligomer accumulation and improves cognition in tauopathy mice. In the present study, we examined the effects of nasal rifampicin on tau propagation in a new mouse model of tauopathy. A tau oligomer-rich fraction prepared from the brain of an AD patient was injected into a unilateral hippocampus of tau264 mice that express both 3-repeat and 4-repeat wild-type human tau. Rifampicin administration was started one week after the injection and performed three times a week for 24 weeks. Cognitive function and tau pathology were assessed by the Morris water maze test and brain section staining. Rifampicin treatment inhibited the spreading of tau oligomers from the injection site to other brain regions and neurofibrillary tangle formation in the entorhinal cortex. Synapse and neuronal loss in the hippocampus were also prevented, and cognitive function remained normal. These results suggest that intranasal rifampicin could be a promising remedy that halts the progression of tauopathy by inhibiting tau oligomer propagation.

RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy.

In Alzheimer’s disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)—which lack Aβ pathology—exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.

The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

Intracellular accumulation of filamentous tau aggregates with progressive neuronal loss is a common characteristic of tauopathies. Although the neurodegenerative mechanism of tau‐associated pathology remains unclear, molecular elements capable of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative progression. Here, we provide evidence that p62/SQSTM1, a ubiquitinated cargo receptor for selective autophagy, acts protectively against neuronal death and neuroinflammation provoked by abnormal tau accumulation. P301S mutant tau transgenic mice (line PS19) exhibited accumulation of neurofibrillary tangles with localization of p62 mostly in the brainstem, but neuronal loss with few neurofibrillary tangles in the hippocampus. In the hippocampus of PS19 mice, the p62 level was lower compared to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied by co‐localization of p62 was observed. In PS19 mice deficient in p62 (PS19/p62‐KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed in the hippocampus as compared with PS19 mice. In addition, increase of abnormal tau and neuroinflammation were observed in the brainstem of PS19/p62‐KO. Immunostaining and dot‐blot analysis with an antibody selectively recognizing tau dimers and higher‐order oligomers revealed that oligomeric tau species in PS19/p62‐KO mice were significantly accumulated as compared to PS19 mice, suggesting the requirement of p62 to eliminate disease‐related oligomeric tau species. Our findings indicated that p62 exerts neuroprotection against tau pathologies by eliminating neurotoxic tau species, suggesting that the manipulative p62 and selective autophagy may provide an intrinsic therapy for the treatment of tauopathy. This study proposes a mechanism that p62/SQSTM1, a ubiquitinated cargo receptor for selective autophagy, acts protectively against neuronal death and neuroinflammation as tau pathologies by eliminating disease‐related oligomeric tau formed during the aggregation process of abnormal tau.

Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown. This review summarizes recent findings regarding the role of tau oligomers in disease, including release from cells, propagation from affected to unaffected brain regions, uptake into cells, and toxicity via mitochondrial dysfunction. A greater understanding of tauopathies may lead to future advancements in regards to prevention and treatment.

Background Amyloid aggregate deposition is the key feature of Alzheimer’s disease. The proteinaceous aggregates found in the afflicted brain are the intra-neuronal neurofibrillary tangles formed by the microtubule-associated protein Tau and extracellular deposits, senile plaques, of amyloid beta (Aβ) peptide proteolytically derived from the amyloid precursor protein. Accumulation of these aggregates has manifestations in the later stages of the disease, such as memory loss and cognitive inabilities originating from the neuronal dysfunction, neurodegeneration, and brain atrophy. Treatment of this disease at the late stages is difficult, and many clinical trials have failed. Hence, the goal is to find means capable of preventing the aggregation of these intrinsically disordered proteins by inhibiting the early stages of their pathological transformations. Polyphenols are known to be neuroprotective agents with the noticeable potential against many neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Prion diseases. Methods We analyzed the capability of Baicalein to inhibit aggregation of human Tau protein by a multifactorial analysis that included several biophysical and biochemical techniques. Results The potency of Baicalein, a polyphenol from the Scutellaria baicalensis Georgi , against in vitro Tau aggregation and PHF dissolution has been screened and validated. ThS fluorescence assay revealed the potent inhibitory activity of Baicalein, whereas ANS revealed its mechanism of Tau inhibition viz. by oligomer capture and dissociation. In addition, Baicalein dissolved the preformed mature fibrils of Tau thereby possessing a dual target action. Tau oligomers formed by Baicalein were non-toxic to neuronal cells, highlighting its role as a potent molecule to be screened against AD. Conclusion In conclusion, Baicalein inhibits aggregation of hTau40 by enhancing the formation of SDS-stable oligomers and preventing fibril formation. Baicalein-induced oligomers do not affect the viability of the neuroblastoma cells. Therefore, Baicalein can be considered as a lead molecule against Tau pathology in AD. 7WG9tgRW_24b19dTX7j1bj Video Abstract

The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer’s disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood–brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.