Tau Expression Research Articles

Effect of calcium ions on the aggregation of highly phosphorylated tau

Tau is typically an axonal protein, but in neurons of brains affected by Alzheimer's disease (AD), aggregation of hyperphosphorylated tau in the somatodendritic compartment causes neuronal death. We have previously demonstrated that tau mRNA is transported within dendrites and undergoes immediate translation and hyperphosphorylation of AD epitopes in response to NMDA receptor stimulation. Although this explains the emergence of hyperphosphorylated tau in dendrites, the relationship between tau hyperphosphorylation and aggregation is not well understood. In this study, we found that recombinant highly phosphorylated tau purified from NG108-15 rodent neuroblastoma/glioma cells transfected with both tau and GSK3β expression vectors bound calcium ions and formed sarkosyl-insoluble aggregates. In addition, thioflavin T analysis revealed that this highly phosphorylated tau tended to aggregate on its own, further facilitated by calcium ions. When NG108-15 cells expressing the highly phosphorylated tau were treated with calcium ionophore, sarkosyl-insoluble tau was generated. Interestingly, these cells exhibited resistance to both calcium ionophore-induced cytotoxicity and glutamate-induced excitotoxicity. We further found that sarkosyl-insoluble phosphorylated tau was increased in cultured hippocampal neurons due to glutamate-induced hyperactivity. Our data suggest that hyperphosphorylated tau synthesized in response to NMDA receptor stimulation contributes to regulation of neuronal activity by binding calcium ions, but that this calcium binding may cause tau to adopt an aggregated form.

Development of MAPT S305 mutation human iPSC lines exhibiting elevated 4R tau expression and functional alterations in neurons and astrocytes

Due to the importance of 4R tau (with four microtubule-binding-repeat domains) in the pathogenicity of primary tauopathies, it has been challenging to model these diseases in induced pluripotent stem cell (iPSC)-derived neurons, which express very low levels of 4R tau. To address this, we have developed a panel of isogenic iPSC lines carrying MAPT splice-site mutations, S305S, S305I, or S305N, derived from four different donors. All mutations significantly increase 4R tau expression in iPSC neurons and astrocytes. Functional analyses of S305 mutant neurons reveal shared disruption in synaptic signaling and maturity but divergent effects on mitochondrial bioenergetics. In iPSC astrocytes, S305 mutations promote internalization of exogenous tau that may be a precursor to glial pathology. These lines recapitulate previously characterized tauopathy-relevant phenotypes and highlight functional differences between the wild-type 4R and the mutant 4R proteins in both neurons and astrocytes. As such, these lines enable a more complete understanding of pathogenic mechanisms underlying 4R tauopathies across different cell types.

Marmosets as model systems for the study of Alzheimer's disease and related dementias: Substantiation of physiological tau 3R and 4R isoform expression and phosphorylation.

Marmosets spontaneously develop pathological hallmarks of Alzheimer's disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied. Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization in the soma and synaptic regions. Phosphorylation residues were observed on Threonine (Thr) Thr181, Thr217, Thr231, Serine (Ser) Ser202/Thr205, and Ser396/Ser404. Our results confirm both 3R and 4R tau isoform expression and phosphorylation residues in the marmoset brain, and emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for AD. Highlights We report comprehensive characterization of tau isoform expression in marmoset brains across the lifespan. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. These data emphasize the significance of marmosets with natural expression of primate-specific traits that are important for the study of Alzheimer's disease.

Effects of Ficus exasperata on neurotransmission and expression of BDNF, tau, ACHE and BACE in diabetic rats

Diabetes mellitus, a chronic metabolic disorder, has significant global health implications, particularly due to its neurological complications, such as diabetic neuropathy. This condition increases the risk of neurodegenerative diseases by affecting peripheral nerves and cognition. Ficus exasperata, known for its neuroprotective properties, shows promise as a therapeutic option for addressing these complications. This study evaluates the effects of methanol extract of Ficus exasperata (MEFE) on neurotransmission and the expression of Tau, brain-derived neurotrophic factor (BDNF), acetylcholinesterase (ACHE), and Beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) in alloxan-induced diabetic Wistar rats. The controlled experimental design involved 20 Wistar rats divided into four groups (n = 5): control, diabetic untreated, diabetes + MEFE (200 mg/kg), and diabetes + insulin (0.3 IU). The methanol extract was prepared using cold maceration, and an aliquot was subjected to gas chromatography-mass spectrometry. Constituents of MEFE were docked with neurologic receptors. Blood glucose levels were measured using the glucose oxidase method, and neurotransmitter levels, antioxidants, oxidative stress markers, and the expression of Tau, BDNF, ACHE, and BACE were assessed using standard procedures and qRT-PCR. Data were analyzed using one-way ANOVA at P < 0.05. Results indicated that MEFE significantly reduced fasting blood glucose levels compared to untreated diabetic rats. In silico docking identified kaur-16-ene, a constituent of MEFE, as having the highest binding affinity for NMDA, TrkB, mAchR and nAchR receptors, indicating its neuroprotective potential. MEFE also enhanced antioxidant enzyme levels (SOD, GPx, catalase) while reducing oxidative stress markers (MDA, 8-OHdG). Gene expression analysis revealed that MEFE modulates the expression of Tau, BDNF, ACHE, and BACE, suggesting its potential to influence neurodegenerative pathways associated with diabetic neuropathy. Ficus exasperata demonstrates significant therapeutic potential in managing diabetic neuropathy and related cognitive impairments by modulating neurotransmission, protein expression, and antioxidant defenses.

Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models

AimsTo investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets. MethodsWe systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models. ResultsBehavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level. ConclusionsSemaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.

Subtype-specific neurons from patient iPSCs display distinct neuropathological features of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain. Both cortical glutamatergic neurons and basal forebrain cholinergic neurons (BFCNs) in the AD brain are selectively vulnerable. The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients. The determination of cellular and molecular mechanisms involved in AD pathogenesis, especially in the early stage, will largely facilitate the understanding of this disease and the development of proper intervention strategies. However, due to the inaccessibility of living neurons in the brains of patients, it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD. In this study, we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs. We found that AD-BFCNs secreted less Aβ peptide than cortical glutamatergic neurons did, even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons. To further mimic the neurotoxic niche in AD brain, we treated iPSC-derived neurons with Aβ42 oligomer (AβO). BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons. However, AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs. In addition, AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment. These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD, which might help to understand AD pathogenesis at the cellular level.

AAV8-P301L tau expression confers age-related disruptions in sleep quantity and timing

Sleep timing and quantity disturbances persist in tauopathy patients. This has been studied in transgenic models of primary tau neuropathology using traditional electroencephalograms (EEGs) and more recently, the PiezoSleep Mouse Behavioral Tracking System. Here, we generated a primary tauopathy model using an intracerebroventricular injection of human mutant hSyn-P301L-tau, using adeno-associated virus of serotype 8 (AAV8). We discovered distinctions in sleep architecture with altered quantity and timing in AAV8-P301L tau expressing mice of both sexes using the noninvasive PiezoSleep System. The AAV8-P301L tau mice exhibit striking age-related increases in sleep duration specifically at the active phase onset, suggesting a critical and sensitive time-of-day for tauopathy related sleep disturbances to occur. Since our findings show sleep behavior changes at specific transitional periods of the day, tau neuropathology may impact normal diurnal variation in biological processes, which should be explored using the AAV8-P301L tauopathy model.

In-situ nanozyme catalytic amplification coupled with a universal antibody orientation strategy based electrochemical immunosensor for AD-related biomarker

An in-situ nanozyme signal tag combined with a DNA-mediated universal antibody-oriented strategy was proposed to establish a high-performance immunosensing platform for Alzheimer's disease (AD)-related biomarker detection. Briefly, a Zr-based metal-organic framework (MOF) with peroxidase (POD)-like activity was synthesized to encapsulating the electroactive molecule methylene blue (MB), and subsequently modified with a layer of gold nanoparticles on its surface. This led to the creation of double POD-like activity nanozymes surrounding the MB molecule to form a nanozyme signal tag. A large number of hydroxyl radicals were generated by the nanozyme signal tag with the help of H2O2, which catalyzed MB molecules in situ to achieve efficient signal amplification. Subsequently, a DNA-aptamer-mediated universal antibody-oriented strategy was proposed to enhance the binding efficiency for the antigen (target). Meanwhile, a poly adenine was incorporated at the end of the aptamer, facilitating binding to the gold electrode and providing anti-fouling properties due to the hydrophilicity of the phosphate group. Under optimal conditions, this platform was successfully employed for highly sensitive detection of AD-associated tau protein and BACE1, achieving limits of detection with concentrations of 3.34 fg/mL and 1.67 fg/mL, respectively. It is worth mentioning that in the tau immunosensing mode, 20 clinical samples from volunteers of varying ages were analyzed, revealing significantly higher tau expression levels in the blood samples of elderly volunteers compared to young volunteers. This suggests that the developed strategy holds great promise for early AD diagnosis.

Treatment of Parkinson's disease model with human umbilical cord mesenchymal stem cell-derived exosomes loaded with BDNF

AimsParkinson's disease (PD) is a common neurodegenerative disease that has received widespread attention; however, current clinical treatments can only relieve its symptoms, and do not effectively protect dopaminergic neurons. The purpose of the present study was to investigate the therapeutic effects of human umbilical cord mesenchymal stem cell-derived exosomes loaded with brain-derived neurotrophic factor (BDNF-EXO) on PD models and to explore the underlying mechanisms of these effects. Main methods6-Hydroxydopamine was used to establish in vivo and in vitro PD models. Western blotting, flow cytometry, and immunofluorescence were used to detect the effects of BDNF-EXO on apoptosis and ferroptosis in SH-SY5Y cells. The in vivo biological distribution of BDNF-EXO was detected using a small animal imaging system, and dopaminergic neuron improvements in brain tissue were detected using western blotting, immunofluorescence, immunohistochemistry, and Nissl and Prussian blue staining. Key findingsBDNF-EXO effectively suppressed 6-hydroxydopamine-induced apoptosis and ferroptosis in SH-SY5Y cells. Following intravenous administration, BDNF-EXO crossed the blood–brain barrier to reach afflicted brain regions in mice, leading to a notable enhancement in neuronal survival. Furthermore, BDNF-EXO modulated microtubule-associated protein 2 and phosphorylated tau expression, thereby promoting neuronal cytoskeletal stability. Additionally, BDNF-EXO bolstered cellular antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 signaling pathway, thereby conferring neuroprotection against damage. SignificanceThe novel drug delivery system, BDNF-EXO, had substantial therapeutic effects in both in vivo and in vitro PD models, and may represent a new treatment strategy for PD.

Fecal microbiome transplantation alleviates manganese-induced neurotoxicity by altering the composition and function of the gut microbiota via the cGAS–STING/NLRP3 pathway

Manganese (Mn) is an environmental pollutant, and overexposure can cause neurodegenerative disorders similar to Alzheimer's disease and Parkinson's disease that are characterized by β-amyloid (Aβ) overexpression, Tau hyperphosphorylation and neuroinflammation. However, the mechanisms of Mn neurotoxicity are not clearly defined. In our study, a knockout mouse model of Mn exposure combined with gut flora-induced neurotoxicity was constructed to investigate the effect of gut flora on Mn neurotoxicity. The results showed that the levels of Tau, p-Tau and Aβ in the hippocampus of C57BL/6 mice were greater than those in the hippocampus of control mice after 5 weeks of continuous exposure to manganese chloride (Mn content of 200 mg/L). Transplanted normal and healthy fecal microbiota from mice significantly downregulated Tau, p-Tau and Aβ expression and ameliorated brain pathology. Moreover, Mn exposure activated the cGAS–STING pathway and altered the cecal microbiota profile, characterized by an increase in Clostridiales, Pseudoflavonifractor, Ligilactobacillus and Desulfovibrio, and a decrease in Anaerotruncus, Eubacterium_ruminantium_group, Fusimonas and Firmicutes, While fecal microbiome transplantation (FMT) treatment inhibited this pathway and restored the microbiota profile. FMT alleviated Mn exposure-induced neurotoxicity by inhibiting activation of the NLRP3 inflammasome triggered by overactivation of the cGAS–STING pathway. Deletion of the cGAS and STING genes and FMT altered the gut microbiota composition and its predictive function. Phenotypic prediction revealed that FMT markedly decreased the abundances of anaerobic and stress-tolerant bacteria and significantly increased the abundances of facultative anaerobic bacteria and biofilm-forming bacteria after blocking the cGAS–STING pathway compared to the Mn-exposed group. FMT from normal and healthy mice ameliorated the neurotoxicity of Mn exposure, possibly through alterations in the composition and function of the microbiome associated with the cGAS–STING/NLRP3 pathway. This study provides a prospective direction for future research on the mechanism of Mn neurotoxicity.

Severe neurodegeneration in brains of transgenic rats producing human tau prions

Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion–mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer’s disease and other tau prion disorders.

Glucose uptake in pigment glia suppresses tau-induced inflammation and photoreceptor degeneration in Drosophila.

Tau expression in the fly retina induces glial activationPigment glial cells mediate inflammatory phenotypes in the degenerating retinaEnhanced glucose uptake in the pigment glia suppresses inflammation and photoreceptor neurodegeneration caused by tau expression.

Neuroprotective effects of resveratrol through modulation of PI3K/Akt/GSK-3β pathway and metalloproteases.

To analyze the expressional changes in the PI3K/Akt/GSK-3β pathway and metalloprotease in the cellular Alzheimer's Disease (AD) model with the effect of antioxidant resveratrol. Neuron-like cells were obtained by a two-step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain-derived factor (BDNF) exposure. Then, the application of the amyloid beta peptide 25-35 (Aβ25-35) to the cell culture mimicked the environmental toxicity observed in AD. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, the expressional changes in genes in the cellular AD model with the effect of resveratrol were analyzed by Real-Time PCR. The analysis in silico was assessed using the STRING V12.0 database in each group. Apoptosis data findings were decreased by 1.5-fold and 2.5-fold respectively by Differentiated+Resveratrol (RES) and RES when compared to control but no significant difference was observed between RES and AD model groups. Real-time PCR analysis results revealed PI3K (3.38-fold), AKT (3.95-fold), and RELN (1.99-fold) expressions were significantly higher (p < .001), and also GSK-3β, TAU, ADAMTS-4, ADAMTS-5, and TIMP-3 gene expression levels were significantly downregulated (2.53-, 1.79-, 2.85-, 4.09-, and 6.62-fold, respectively) in the Differentiated+Aβ + RES groups compared to the Differentiated+Aβ group (p < .001). Network analysis shows the functional enrichment of 23 Alzheimer-related GO terms in the Wnt signaling, proteolysis, and extracellular matrix organization pathways. Resveratrol has inhibited GSK-3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.

Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer’s disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP.

Preclinical efficacy of oral and nasal rivastigmine-loaded chitosan nano-particles on AlCl3-induced Alzheimer’s-like disease in rats

The successful treatment of Alzheimer’s disease (AD) is still a big challenge. Rivastigmine is one of the most used drugs for the treatment of AD. The short half-life, lower bioavailability, and less concentration of the drug in the brain after oral delivery are considered the main drawbacks of rivastigmine. To improve these drawbacks, nanostructure-mediated drug delivery has gained more attention. This study investigates the effect of rivastigmine-loaded in optimized chitosan nano-particles (RS-CSNPs) as polymeric nano-carriers by different administration routes (oral and intranasal) on aluminum chloride (AlCl3)-induced Alzheimer-like disease in rat. The model was established by giving rats 100 mg/kg/b.wt of AlCl3 orally for 3 months. Then the experimental rats were treated with RS-CSNPs either orally or intranasally for 75 days. Histopathology, immunohistochemistry of Tau expression in brain tissue, and gene expression of Caspase-3, NF-κB, and Nrf-2 were carried out. The therapeutic agents used decreased the alterations observed in AlCl3 group with improvement in the neuronal viability. In addition to low expression of tau protein, down-regulation of caspase-3 and NF-κB genes and up-regulation of Nrf-2. RS-CSNPs alleviated the progression of AD presumably via blocking the inflammatory cascade and decreasing the oxidative stress process. The intranasal route is superior to the oral one and promising in AD management.

The big tau splice isoform resists Alzheimer's-related pathological changes.

In Alzheimer's disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus 1-3 . However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed "big tau" is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.

Neuronal expression of human amyloid-β and Tau drives global phenotypic and multi-omic changes in C. elegans.

Alzheimer's disease (AD) and Alzheimer's related diseases (ADRD) are prevalent age-related neurodegenerative disorders characterized by the accumulation of amyloid-β (Aβ) plaques and Tau neurofibrillary tangles. The nematode Caenorhabditis elegan s ( C. elegans ) serves as an invaluable model organism in diseases of old age-due to its rapid aging. Here we performed an unbiased systems analysis of a C. elegans strain expressing both Aβ and Tau proteins within neurons. We set out to determine if there was a phenotypic interaction between Aβ and Tau. In addition, we were interested in determining the temporal order of the phenotypic and multi-omic (geromic) outcomes. At an early stage of adulthood, we observed reproductive impairments and mitochondrial dysfunction consistent with disruptions in mRNA transcript abundance, protein solubility, and metabolite levels. Notably, the expression of these neurotoxic proteins exhibited a synergistic effect, leading to accelerated aging. Our findings shed light on the close relationship between normal aging and ADRD. Specifically, we demonstrate alterations to metabolic functions preceding age-related neurotoxicity, offering a resource for the development of new therapeutic strategies.

Cytoplasmic aggregation of TDP43 and topographic correlation with tau and α-synuclein accumulation in the rTg4510 mouse model of tauopathy.

In patients with TDP43 proteinopathy, phosphorylated TDP43 (p-TDP43) accumulates in the cytoplasm of neurons. The accumulation of p-TDP43 has also been reported in patients with tauopathy and α-synucleinopathy. We investigated spatiotemporal changes in p-TDP43 accumulation in the brains of rTg4510 mice that overexpressed human mutant tau (P301L) and exhibited hyperphosphorylated tau (hp-tau) and phosphorylated αSyn (p-αSyn) accumulation. Immunohistochemically, p-TDP43 aggregates were observed in the cytoplasm of neurons, which increased with age. A significant positive correlation was observed between the number of cells with p-TDP43 aggregates and hp-tau and p-αSyn aggregates. Suppression of the human mutant tau (P301L) expression by doxycycline treatment reduces the accumulation of p-TDP43, hp-tau, and p-αSyn. Proteinase K-resistant p-TDP43 aggregates were found in regions with high hp-tau, and p-αSyn accumulation. Western blotting of the sarkosyl-insoluble fraction revealed bands of monomeric TDP43 and p-TDP43. These results indicate that the accumulation of mouse p-TDP43 is associated with the accumulation of human mutant tau (P301L) in rTg4510 mouse brains. The accumulation of hp-tau and p-αSyn may promote sarkosyl-insoluble p-TDP43 aggregates that are resistant to proteinase K. The synergistic effects of tau, TDP43, and αSyn may be involved in the pathology of proteinopathies, leading to the accumulation of multiple abnormal proteins.

Selective degradation of hyperphosphorylated tau by proteolysis-targeting chimeras ameliorates cognitive function in Alzheimer's disease model mice.

Alzheimer's disease (AD) is one of the most common chronic neurodegenerative diseases. Hyperphosphorylated tau plays an indispensable role in neuronal dysfunction and synaptic damage in AD. Proteolysis-targeting chimeras (PROTACs) are a novel type of chimeric molecule that can degrade target proteins by inducing their polyubiquitination. This approach has shown promise for reducing tau protein levels, which is a potential therapeutic target for AD. Compared with traditional drug therapies, the use of PROTACs to reduce tau levels may offer a more specific and efficient strategy for treating AD, with fewer side effects. In the present study, we designed and synthesized a series of small-molecule PROTACs to knock down tau protein. Of these, compound C8 was able to lower both total and phosphorylated tau levels in HEK293 cells with stable expression of wild-type full-length human tau (termed HEK293-htau) and htau-overexpressed mice. Western blot findings indicated that C8 degraded tau protein through the ubiquitin-proteasome system in a time-dependent manner. In htau-overexpressed mice, the results of both the novel object recognition and Morris water maze tests revealed that C8 markedly improved cognitive function. Together, our findings suggest that the use of the small-molecule PROTAC C8 to degrade phosphorylated tau may be a promising therapeutic strategy for AD.

Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype

The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.