Transmission Of Tau Research Articles

Arc mediates intercellular tau transmission via extracellular vesicles.

Intracellular neurofibrillary tangles that consist of misfolded tau protein 1 cause neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau pathology spreads cell-to-cell 2 but the exact mechanisms of tau release and intercellular transmission remain poorly defined. Tau is released from neurons as free protein or in extracellular vesicles (EVs) 3-5 but the role of these different release mechanisms in intercellular tau transmission is unclear. Here, we show that the neuronal gene Arc is critical for packaging tau into EVs. Brain EVs purified from human tau (hTau) transgenic rTg4510 mice (rTg WT ) contain high levels of hTau that are capable of seeding tau pathology. In contrast, EVs purified from rTg WT crossed with Arc knock-out mice (rTg Arc KO ) have significantly less hTau and cannot seed tau aggregation. Arc facilitates the release of hTau in EVs produced via the I-BAR protein IRSp53, but not free tau. Arc protein directly binds hTau to form a fuzzy complex that we identified in both mouse and human brain tissue. We find that pathological intracellular hTau accumulates in neurons in rTg Arc KO mice, which correlates with accelerated neuron loss in the hippocampus. Finally, we find that intercellular tau transmission is significantly abrogated in Arc KO mice. We conclude that Arc-dependent release of tau in EVs plays a significant role in intracellular tau elimination and intercellular tau transmission.

Directionality bias underpins divergent spatiotemporal progression of Alzheimer-related tauopathy in mouse models.

Mounting evidence implicates trans-synaptic connectome-based spread as a shared mechanism behind different tauopathic conditions, yet also suggests there is divergent spatiotemporal progression between them. A potential parsimonious explanation for this apparent contradiction could be that different conditions incur differential rates and directional biases in tau transmission along fiber tracts. In this meta-analysis we closely examined this hypothesis and quantitatively tested it using spatiotemporal tau pathology patterns from 11 distinct models across 4 experimental studies. For this purpose, we extended a network-based spread model by incorporating net directionality along the connectome. Our data unambiguously supports the directional transmission hypothesis. First, retrograde bias is an unambiguously better predictor of tau progression than anterograde bias. Second, while spread exhibits retrograde character, our best-fitting biophysical models incorporate the mixed effects of both retrograde- and anterograde-directed spread, with notable tau-strain-specific differences. We also found a nontrivial association between directionality bias and tau strain aggressiveness, with more virulent strains exhibiting less retrograde character. Taken together, our study implicates directional transmission bias in tau transmission along fiber tracts as a general feature of tauopathy spread and a strong candidate explanation for the diversity of spatiotemporal tau progression between conditions. This simple and parsimonious mechanism may potentially fill a critical gap in our knowledge of the spatiotemporal ramification of divergent tauopathies.

Tau induces inflammasome activation and microgliosis through acetylating NLRP3.

Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule-associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. The levels of nucleotide-binding oligomerisation domain(NOD)-like receptor pyrin domain containing 3(NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme-linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test-tube acetylation assay, co-immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau-overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno-associated virus injection. The cognitive functions of Tau-overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba-1 IF staining and [18F]-DPA-714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau-NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg-AD mice, microtubule-associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated-Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau-K18 domain acetyltransferase activity-dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV-2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau-NLRP3-binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

Galectin-3 aggravates microglial activation and tau transmission in tauopathy.

Alzheimer's disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.

A role of tau‐induced astrocyte dysfunction and senescence in AD

AbstractBackgroundUnder certain conditions and during aging, cellular stress and damage can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the “senescent‐associated secretory phenotype” (SASP). In Alzheimer’s disease (AD), neuronal tau becomes hyperphosphorylated and misfolded, forming pathogenic soluble aggregates (tau oligomers) and destabilizing the microtubule cytoskeleton. Pathogenic soluble tau is released from neurons during neuronal activation and is transmitted in a prion‐like fashion to postsynaptic cells. In addition to neurons, tau is expressed in a variety of brain cell types including astrocytes. In the present study, we tested the central hypothesis that soluble pathogenic tau can be transmitted to astrocytes and that tau transmission to astrocytes induces cytoskeleton destabilization and cellular dysfunction, contributing to the progression of AD.MethodsTo test the molecular consequences of tau transmission, we treated primary human astrocytes with purified tau oligomers. We used advanced biochemical tools, immunocytochemistry, and live‐cell microscopy to measure cell and nuclear size, cell cycle arrest, and SASP activation. We also co cultured human astrocytes undergoing tau‐induced senescence with primary mouse or non‐human primate neurons to determine the functional impact of senescent astrocytes on neurons, then utilized immunocytochemistry and 3D image analyses to measure parameters of dendrite and spine morphology.ResultsWe found that pathogenic soluble tau is readily transmitted to primary human astrocytes, and that pathogenic tau transmission triggers phosphorylation of endogenous astrocyte tau, leading to the destabilization of the microtubule cytoskeleton. Further, we found that transmission of pathogenic tau to astrocytes potently upregulated multiple markers of cellular senescence, demonstrating for the first time tau‐induced astrocyte senescence. Density of dendritic spines and dendritic area were pronouncedly decreased in neurons co‐cultured with astrocytes undergoing tau‐induced senescence.ConclusionWe showed transmission of pathogenic tau to human astrocytes and that this event triggers astrocyte senescence in mouse models of AD tauopathy. Our data suggest that senescent astrocytes may be critical mediators of neuronal dysfunction in AD tauopathy.

Inhibition of EV biogenesis reduces tau propagation in Alzheimer’s Disease mouse models

AbstractBackgroundMounting evidence correlates the propagation of hyperphosphorylated tau (pTau) along synaptically connected networks in the brain with progressive cognitive decline in Alzheimer’s Disease (AD). Recent findings have highlighted extracellular vesicle (EV)s in enabling transcellular transmission of pathological tau and identified the partial inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, there are no suitable compounds for clinical development so far.MethodThrough high‐throughput screening, we identified PDDC, a highly selective and potent nSMase2 inhibitor with excellent brain penetration and oral bioavailability. To evaluate PDDC’s effect on tau propagation in vivo, we chronically administered PDDC‐containing chow to PS19 transgenic mice and measured brain ceramides, nSMase2 activity, tau levels, glial activation, hippocampal neuronal cell layer thickness, and mossy fiber synaptophysin staining. In addition, neuronally‐derived EVs from plasma were isolated and characterized. To directly monitor the effect of PDDC on tau propagation, we developed a murine model where an AAV encoding for P301L/S320F double mutant human tau was stereotaxically‐injected unilaterally into the hippocampus and transfer to the contralateral dentate gyrus (DG) was monitored ± PDDC treatment.ResultPS19 mice exhibited robust elevation of multiple ceramide species and nSMase2 enzymatic activity in the brain, both of which were normalized by PDDC treatment. PS19 mice treated with PDDC had significantly reduced hippocampal total tau and Thr181 pTau, reduced glial activation, protected synapses, and improved pyramidal and granule cell layer thickness. Plasma NEVs of treated mice were fewer in number and had lower p181‐Tau levels than the untreated group; FCA confirmed the decrease of NEVs carrying p262‐Tau at the single EV level. Similarly, the AAV‐hTau‐seeded mice treated with PDDC had reduced tau staining intensity in the contralateral DG.ConclusionData in two AD models using PDDC provides strong preclinical support for using nSMase2 inhibition as a therapeutic strategy to slow tau propagation in AD.

Pathogenic Role of RAGE in Tau Transmission and Memory Deficits

BackgroundIn tauopathies, brain regions with tau accumulation strongly correlate with clinical symptoms, and spreading of misfolded tau along neural network leads to disease progression. However, the underlying mechanisms by which tau proteins enter neurons during pathological propagation remain unclear. MethodsTo identify membrane receptors responsible for neuronal propagation of tau oligomers, we established a cell-based tau uptake assay and screened complementary DNA expression library. Tau uptake and propagation were analyzed in vitro and in vivo using a microfluidic device and stereotactic injection. The cognitive function of mice was assessed using behavioral tests. ResultsFrom a genome-wide cell-based functional screening, RAGE (receptor for advanced glycation end products) was isolated to stimulate the cellular uptake of tau oligomers. Rage deficiency reduced neuronal uptake of pathological tau prepared from rTg4510 mouse brains or cerebrospinal fluid from patients with Alzheimer’s disease and slowed tau propagation between neurons cultured in a 3-chamber microfluidic device. RAGE levels were increased in the brains of rTg4510 mice and tau oligomer-treated neurons. Rage knockout decreased tau transmission in the brains of nontransgenic mice after injection with Alzheimer’s disease patient-derived tau and ameliorated memory loss after injection with GFP-P301L-tau-AAV. Treatment of RAGE antagonist FPS-ZM1 blocked transsynaptic tau propagation and inflammatory responses and alleviated cognitive impairment in rTg4510 mice. ConclusionsThese results suggest that in neurons and microglia, RAGE binds to pathological tau and facilitates neuronal tau pathology progression and behavioral deficits in tauopathies.

Cofilin promotes tau pathology in Alzheimer's disease.

The molecular mechanisms mediating the aggregation and transmission of tau in AD remain unclear. Here, we show that the actin-binding protein cofilin is cleaved by a cysteine protease asparagine endopeptidase (AEP) at N138 in the brains of patients with AD. The AEP-generated cofilin 1-138 fragment interacts with tau and promotes its aggregation. The mixed fibrils consisting of cofilin 1-138 and tau are more pathogenic to cells than pure tau fibrils. Furthermore, overexpression of cofilin 1-138 in the brain facilitates the propagation of pathological tau aggregates and promotes AD-like cognitive impairments in tau P301S mice. However, mice infected with adeno-associated viruses (AAVs) encoding an AEP-uncleavable cofilin mutant show attenuated tau pathology and cognitive impairments compared with mice injected with AAVs encoding wild-type cofilin. Together, these observations support the role of the cofilin 1-138 fragment in the aggregation and transmission of tau pathology during the onset and progression of AD.

Blocking tau transmission by biomimetic graphene nanoparticles.

Tauopathies are a class of neurodegenerative diseases resulting in cognitive dysfunction, executive dysfunction, and motor disturbance. The primary pathological feature of tauopathies is the presence of neurofibrillary tangles in the brain composed of tau protein aggregates. Moreover, tau aggregates can spread from neuron to neuron and lead to the propagation of tau pathology. Although numerous small molecules are known to inhibit tau aggregation and block tau cell-to-cell transmission, it is still challenging to use them for therapeutic applications due to poor specificity and low blood-brain barrier (BBB) penetration. Graphene nanoparticles were previously demonstrated to penetrate the BBB and are amenable to functionalization for targeted delivery. Moreover, these nanoscale biomimetic particles can self-assemble or assemble with various biomolecules including proteins. In this paper, we show that graphene quantum dots (GQDs), as graphene nanoparticles, block the seeding activity of tau fibrils by inhibiting the fibrillization of monomeric tau and triggering the disaggregation of tau filaments. This behavior is attributed to electrostatic and π-π stacking interactions of GQDs with tau. Overall, our studies indicate that GQDs with biomimetic properties can efficiently inhibit and disassemble pathological tau aggregates, and thus block tau transmission, which supports their future developments as a potential treatment for tauopathies.

Development of iPSC‐derived AD platforms for phenotypic screening

AbstractBackgroundHuman iPSC‐derived in vitro neural co‐culture systems have been used increasingly in drug discovery for neurological and neurodegenerative disorders.MethodHere we describe the development of iPSC‐derived platforms of AD that can be used to screen for preclinical targets and drug candidates. The foundation of these platforms utilizes a proprietary method for the generation of pure populations of NGN2‐based excitatory and ASCL1/DLX2 inhibitory neurons.ResultTransgenic overexpression of tau isoforms leads to prion‐like tau spreading that can be used to screen for compounds to mitigate tau propagation. Using this platform, we investigated how tau overexpression leads to neuron‐neuron tau transmission, alters neuron electrophysiology as assessed by MEA, and leads to the accumulation of key neuropathological tau biomarkers. In addition, we have developed co‐culture platforms that facilitate examination of the role of neuroinflammation on the development of key neuropathological hallmarks of AD. This platform can be used in conjunction with isogenic iPSCs to interrogate the mechanism by which genetic risk factors confer increased or decreased AD risk.ConclusionTaken together, these phenotypic assays demonstrate the utility of NeuCyte platforms that can be applied to high‐throughput drug screening efforts for AD.

NSMase2 inhibition reduces tau propagation in Alzheimer’s Disease mouse models

AbstractBackgroundAlzheimer’s Disease (AD) is the most common form of dementia worldwide and is characterized by progressive neurodegeneration and cognitive decline, putatively driven by the accumulation Amyloid‐b and hyperphosphorylated Tau. Clinical trial successes focusing on reducing Amyloid‐b plaque levels in patient brains have been modest, spurring a renewed focus on tau. Tau spreads throughout the brain along anatomical pathways, correlating strongly with the disease progression severity. Recent evidence has highlighted extracellular vesicles (EVs) in enabling transcellular transmission of pathological tau in the brain in a ‘prion‐like’ manner and identified the inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, presently available tool compounds are unsuitable for clinical development.MethodTo improve upon current inhibitors, we performed high‐throughput screening followed by extensive chemistry and identified two classes of compounds. The first, PDDC, has excellent potency, oral bioavailability, and brain penetration, as well as in vitro and in vivo EV inhibition. The second, DPTIP, has higher potency, but poor oral pharmacokinetics and modest brain penetration. To circumvent these limitations, we conjugated DPTIP to a brain‐targeting hydroxyl‐dendrimer delivery system (D‐DPTIP) and demonstrated CNS target engagement following oral dosing. We then chronically administered PDDC and D‐DPTIP to PS19 transgenic mice and WT mice seeded with an AAV‐hTau vector unilaterally stereotaxically injected into the CA1 hippocampal region. After chronic dosing, we quantified the levels of phosphorylated tau in the hippocampus in the PS19s and the contralateral dentate gyrus in the AAV‐hTau seeded model. We also characterized isolated neuronally‐derived plasma EVs from these mice.ResultPS19 mice treated with PDDC had significantly reduced hippocampal tau and increased neuronal counts compared with vehicle. Additionally, PDDC treatment reduced the release of neuronally‐derived EVs into circulation with lower tau level trends. Similarly, seeded mice treated with either PDDC or D‐DPTIP had reduced tau staining intensity in the contralateral dentate gyrus. Importantly, neither compound induced significant toxicity in either model.ConclusionObserving significant reductions in tau burden in two separate AD models provides proof of concept for nSMase2 inhibition in slowing tau propagation, highlighting the promise of tested compounds as potential AD therapeutics.

The role of human microglia and microglial LRRK2 in tau pathogenesis

AbstractBackgroundThe G2019S mutation in leucine‐rich repeat kinase 2 (LRRK2) is the most common genetic determinant of Parkinson’s disease (PD), reported in both familial and sporadic PD cases. Even though tau‐positive pathology features prominently in the G2019S PD patients, the role of LRRK2 in tau pathogenesis remains poorly understood. Human microglia – the chief brain‐resident phagocytes of the innate immune system ‐ become one of the highest LRR2K expressing cells upon IFN‐y stimulation. Moreover, microglia have been recently implicated in increasing pathological tau transmission by secreting exosome‐bound, seeding‐competent tau into the extracellular space. Using human iPS‐macrophages, a simple but physiologically relevant and genetically tractable model of human microglia, we set out to define the role of microglial LRRK2 in uptake, degradation, and secretion of disease‐associated tau protein.MethodWe have developed a quantitative phagolysosomal proteolysis assay based on dequenching of DQ‐BSA fluorogenic substrate attached to silica microspheres, allowing us to investigate cell‐autonomous phagocytic and degradative capacity of G2019S, LRRK2 KO and isogenic control iPS‐macrophages. In parallel, we have optimised purification and in vitro aggregation of endotoxin‐free, human recombinant 2N4R tau to study tau‐induced phagolysosomal proteolysis deficits in the said iPS‐macrophages.ResultWe have found that human iPS‐macrophages readily internalize extracellular tau monomer and fibrils, and LRRK2 is required for macrophage uptake of tau monomer. Degradation of internalized tau is concentration and incubation‐length dependent regardless of genotype. However, G2019S macrophages show deficits in degradation of internalized tau fibrils. Moreover, non‐degraded tau fibrils present within G2019S cell‐ lysates 24h post incubation retain seeding competency and induce aggregation of naïve tau monomer in K11 tau RT‐QuIC assay, unlike tau fibrils internalized by LRRK2 KO macrophages.ConclusionLRRK2 expressed by iPS‐macrophages is important for monomeric tau entry, degradation, and seeding capacity of internalized tau fibrils. Future studies will focus on elucidating the molecular mechanisms behind the LRRK2 and tau interaction.

Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies

BackgroundTauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated.MethodsNovel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca2+) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca2+ and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo.ResultsWe observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca2+ release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia.ConclusionsTogether, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca2+ homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies.

The Fate of Tau Aggregates Between Clearance and Transmission.

Neuronal accumulation of mis-folded tau is the pathological hallmark of multiple neurodegenerative disorders, including Alzheimer’s disease. Distinct from amyloid plaques, which appear simultaneously throughout the brain, tau pathology develops first in a specific brain region and then propagates to neuroanatomically connected brain regions, exacerbating the disease. Due to the implication in disease progression, prevention of tau transmission is recognized as an important therapeutic strategy that can halt disease progression in the brain. Recently, accumulating studies have demonstrated diverse cellular mechanisms associated with cell-to-cell transmission of tau. Once transmitted, mis-folded tau species act as a prion-like seed for native tau aggregation in the recipient neuron. In this review, we summarize the diverse cellular mechanisms associated with the secretion and uptake of tau, and highlight tau-trafficking receptors, which mediate tau clearance or cell-to-cell tau transmission.

Combining network spread with protein aggregation correctly recapitulates empirical spatio-temporal progression of Alzheimer's tau pathology.

Alzheimer's disease involves widespread and progressive deposition of misfolded protein tau, likely via "prion-like" trans-neuronal transmission along the brain's structural connectome. It is not well understood how tau aggregation and spread leads to stereotypical progression in the Alzheimer brain. Here we extend our previous Network Diffusion Model (NDM, [1]) to include these critical processes (see Figure 1): a) Tau monomer seeding and production in the entorhinal cortex; b) aggregation of monomers into larger oligomers and then tangles using well-known Smoluchowski equations that were previously successful for amyloid beta and prions [2]. c) These processes were integrated into NDM, whereby anatomic connections govern the transmission of tau between two distant but connected brain regions. This extended model, which we call Aggregation-Network-Diffusion (AND), was then thoroughly tested on empirical data (Table 1): MRI-derived atrophy, AV1451-PET and CSF biomarkers (Ab42, pTau) from ADNI and Korea cohort [3]. AND model exhibits key hallmarks of AD, accurately capturing the spatial distribution of empirical tau (Korea cohort) as well as regional atrophy of ADNI cohort (Figure 2). R values shown in figure are all highly significant (p<0.0001). Next we interrogated different regions serving as seeding site; the best cortical seeding site was entorhinal cortex, while the best subcortical seeding was in amygdala followed by hippocampus. We also fitted the AND model's total tau PET against patients' cerebrospinal fluid phosphorylated tau (p-tau181) profiles as a function of disease progression; we obtained R = 0.37, p < 1e-36. Sensitivity analysis suggests that diffusion rate is far more important than monomer production rate in governing long-term pathology accumulation (Figure 3). This unified quantitative and testable model has the potential to explain observed phenomena. It may also serve as a test-bed for future hypothesis generation and testing in silico, e.g. to mathematically test whether monomer production, aggregation or diffusion is the key bottleneck.

Possible Mechanisms of Tau Spread and Toxicity in Alzheimer's Disease.

Tau is a protein that associates with microtubules (MTs) and promotes their assembly and stability. The protein loses its ability to bind MTs in tauopathies, and detached tau can misfold and induce the pathological changes that characterize Alzheimer’s disease (AD). A growing body of evidence indicates that tauopathies can spread between cells or connected regions. Pathological tau transmission in the brain of patients with AD and other tauopathies is due to the spread of various tau species along neuroanatomically connected regions in a “prion-like” manner. This complex process involves multiple steps of secretion, cellular uptake, transcellular transfer, and/or seeding, but the precise mechanisms of tau pathology propagation remain unclear. This review summarizes the current evidence on the nature of propagative tau species and the possible steps involved in the process of tau pathology spread, including detachment from MTs, degradations, and secretion, and discusses the different mechanisms underlying the spread of tau pathology.

Longitudinal predictive modeling of tau progression along the structural connectome

Tau neurofibrillary tangles, a pathophysiological hallmark of Alzheimer’s disease (AD), exhibit a stereotypical spatiotemporal trajectory that is strongly correlated with disease progression and cognitive decline. Personalized prediction of tau progression is, therefore, vital for the early diagnosis and prognosis of AD. Evidence from both animal and human studies is suggestive of tau transmission along the brains preexisting neural connectivity conduits. We present here an analytic graph diffusion framework for individualized predictive modeling of tau progression along the structural connectome. To account for physiological processes that lead to active generation and clearance of tau alongside passive diffusion, our model uses an inhomogenous graph diffusion equation with a source term and provides closed-form solutions to this equation for linear and exponential source functionals. Longitudinal imaging data from two cohorts, the Harvard Aging Brain Study (HABS) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), were used to validate the model. The clinical data used for developing and validating the model include regional tau measures extracted from longitudinal positron emission tomography (PET) scans based on the 18F-Flortaucipir radiotracer and individual structural connectivity maps computed from diffusion tensor imaging (DTI) by means of tractography and streamline counting. Two-timepoint tau PET scans were used to assess the goodness of model fit. Three-timepoint tau PET scans were used to assess predictive accuracy via comparison of predicted and observed tau measures at the third timepoint. Our results show high consistency between predicted and observed tau and differential tau from region-based analysis. While the prognostic value of this approach needs to be validated in a larger cohort, our preliminary results suggest that our longitudinal predictive model, which offers an in vivo macroscopic perspective on tau progression in the brain, is potentially promising as a personalizable predictive framework for AD.

Human tauopathy-derived tau strains determine the substrates recruited for templated amplification.

Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer’s disease, three-repeat tau in Pick’s disease (PiD) and four-repeat tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryogenic electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and Alzheimer’s disease (AD)-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrate. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.

The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

SUMMARYTau accumulation is a major pathological hallmark of Alzheimer’s disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick’s disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.

Impact of Tau on Neurovascular Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.