Tau Propagation Research Articles

Spreading of Tau Protein Does Not Depend on Aggregation Propensity

The stereotypical progression of Tau pathology during Alzheimer disease has been attributed to trans-neuronal spreading of misfolded Tau proteins, followed by prion-like templated aggregation of Tau. The nature of Tau and the cellular mechanisms of Tau spreading are still under debate. We hypothesized that Tau’s propensity for aggregation would correlate with its ability to spread across synapses and propagate pathology. To study the progressive propagation of Tau proteins in brain regions relevant for Alzheimer disease, we used mice expressing near-physiological levels of full-length human Tau protein carrying pro-aggregant (TauΔK280, TauΔK) or anti-aggregant (TauΔK280-PP, TauΔK−PP) mutations in the entorhinal cortex (EC). To enhance Tau expression in the EC, we performed EC injections of adeno-associated virus (AAV) particles encoding TauΔK or TauΔK−PP. The brains of injected and non-injected EC/TauΔK and EC/TauΔK−PP mice were studied by immunohistological and biochemical techniques to detect Tau propagation to dentate gyrus (DG) neurons and Tau-induced pathological changes. Pro- and anti-aggregant mice had comparable low transgene expression (~0.2 times endogenous mouse Tau). They accumulated human Tau at similar rates and only in expressing EC neurons, including their axonal projections of the perforant path and presynaptic terminals in the molecular layer of the DG. Pro-aggregant EC/TauΔK mice showed misfolded Tau and synaptic protein alterations in EC neurons, not observed in anti-aggregant EC/TauΔK−PP mice. Additional AAV-mediated expression of TauΔK or TauΔK−PP in EC/TauΔK or EC/TauΔK−PP mice, respectively, increased the human Tau expression to ~0.65 times endogenous mouse Tau, with comparable spreading of TauΔK and TauΔK−PP throughout the EC. There was a low level of transcellular propagation of Tau protein, without pathological phosphorylation or misfolding, as judged by diagnostic antibodies. Additionally, TauΔK but not TauΔK−PP expression induced hippocampal astrogliosis. Low levels of pro- or anti-aggregant full-length Tau show equivalent distributions in EC neurons, independent of their aggregation propensity. Increasing the expression via AAV induce local Tau misfolding in the EC neurons, synaptotoxicity, and astrogliosis and lead to a low level of detectable trans-neuronal spreading of Tau. This depends on its concentration in the EC, but, contrary to expectations, does not depend on Tau’s aggregation propensity/misfolding and does not lead to templated misfolding in recipient neurons.

Fiber-specific micro- and macroscopic white matter alterations in progressive supranuclear palsy and corticobasal syndrome

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are characterized by progressive white matter (WM) alterations associated with the prion-like spreading of four-repeat tau, which has been pathologically confirmed. It has been challenging to monitor the WM degeneration patterns underlying the clinical deficits in vivo. Here, a fiber-specific fiber density and fiber cross-section, and their combined measure estimated using fixel-based analysis (FBA), were cross-sectionally and longitudinally assessed in PSP (n = 20), CBS (n = 17), and healthy controls (n = 20). FBA indicated disease-specific progression patterns of fiber density loss and subsequent bundle atrophy consistent with the tau propagation patterns previously suggested in a histopathological study. This consistency suggests the new insight that FBA can monitor the progressive tau-related WM changes in vivo. Furthermore, fixel-wise metrics indicated strong correlations with motor and cognitive dysfunction and the classifiability of highly overlapping diseases. Our findings might also provide a tool to monitor clinical decline and classify both diseases.

Implication of tau propagation on neurodegeneration in Alzheimer's disease.

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer's disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.

Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau

Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW), due to their properties on size-exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sarkosyl-insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of biophysical and bioactivity assays. Sarkosyl-insoluble fibrillar tau comprises abundant paired-helical filaments (PHF) as quantified by electron microscopy (EM) and is more resistant to proteinase K, compared to HMW tau, which is mostly in an oligomeric form. Sarkosyl-insoluble and HMW tau are nearly equivalent in potency in HEK cell bioactivity assay for seeding aggregates, and their injection reveals similar local uptake into hippocampal neurons in PS19 Tau transgenic mice. However, the HMW preparation appears to be far more potent in inducing a glial response including Clec7a-positive rod microglia in the absence of neurodegeneration or synapse loss and promotes more rapid propagation of misfolded tau to distal, anatomically connected regions, such as entorhinal and perirhinal cortices. These data suggest that soluble HMW tau has similar properties to fibrillar sarkosyl-insoluble tau with regard to tau seeding potential, but may be equal or even more bioactive with respect to propagation across neural systems and activation of glial responses, both relevant to tau-related Alzheimer phenotypes.

TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo.

The role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.

Tau protein spreads through functionally connected neurons in Alzheimer's disease: a combined MEG/PET study.

Recent studies on Alzheimer's disease (AD) suggest that tau proteins spread through the brain following neuronal connections. Several mechanisms could be involved in this process: spreading between brain regions that interact strongly (functional connectivity); through the pattern of anatomical connections (structural connectivity); or simple diffusion. Using magnetoencephalography (MEG), we investigated which spreading pathways influence tau protein spreading by modelling the tau propagation process using an epidemic spreading model. We compared the modelled tau depositions with 18F-flortaucipir PET binding potentials at several stages of the AD continuum. In this cross-sectional study, we analysed source-reconstructed MEG data and dynamic 100-min 18F-flortaucipir PET from 57 subjects positive for amyloid-β pathology [preclinical AD (n = 16), mild cognitive impairment (MCI) due to AD (n = 16) and AD dementia (n = 25)]. Cognitively healthy subjects without amyloid-β pathology were included as controls (n = 25). Tau propagation was modelled as an epidemic process (susceptible-infected model) on MEG-based functional networks [in alpha (8-13 Hz) and beta (13-30 Hz) bands], a structural or diffusion network, starting from the middle and inferior temporal lobe. The group-level network of the control group was used as input for the model to predict tau deposition in three stages of the AD continuum. To assess performance, model output was compared to the group-specific tau deposition patterns as measured with 18F-flortaucipir PET. We repeated the analysis by using networks of the preceding disease stage and/or using regions with most observed tau deposition during the preceding stage as seeds. In the preclinical AD stage, the functional networks predicted most of the modelled tau-PET binding potential, with best correlations between model and tau-PET [corrected amplitude envelope correlation (AEC-c) alpha C = 0.584; AEC-c beta C = 0.569], followed by the structural network (C = 0.451) and simple diffusion (C = 0.451). Prediction accuracy declined for the MCI and AD dementia stages, although the correlation between modelled tau and tau-PET binding remained highest for the functional networks (C = 0.384; C = 0.376). Replacing the control-network with the network from the preceding disease stage and/or alternative seeds improved prediction accuracy in MCI but not in the dementia stage. These results suggest that in addition to structural connections, functional connections play an important role in tau spread, and highlight that neuronal dynamics play a key role in promoting this pathological process. Aberrant neuronal communication patterns should be taken into account when identifying targets for future therapy. Our results also suggest that this process is more important in earlier disease stages (preclinical AD/MCI); possibly, in later stages, other processes may be influential.

TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration.

TREM2 is a membrane receptor expressed on microglia that plays a pivotal role in the organization and function of these innate immune cell components within the neurodegenerated brain. Whereas TREM2 deletion has been studied extensively in experimental beta-amyloid and Tau-based models of Alzheimer's disease, its engagement, and subsequent agonism have not been tested in the context of Tau pathology. Herein, we explored the effects of Ab-T1, an agonistic TREM2 monoclonal antibody on Tau uptake, phosphorylation, seeding, and spreading as well as its therapeutic efficacy in a Tauopathy model. Ab-T1 enhanced the uptake of misfolded Tau to microglia and induced a non-cell autonomous attenuation of spontaneous Tau seeding and phosphorylation in primary neurons from human Tau transgenic mice. Ex vivo, incubation with Ab-T1 led to a significant reduction in the seeding of Tau pathology in the hTau murine organoid brain system. Systemic administration of Ab-T1 resulted in reduced Tau pathology and propagation when hTau was stereotactically injected into the hemispheres of hTau mice. Intraperitoneal treatment with Ab-T1 lead to attenuation of cognitive decline in the hTau mice that was associated with reduced neurodegeneration and synaptic preservation with amelioration of the global neuroinflammatory program. Collectively, these observations show that TREM2 engagement with an agonistic antibody result in reduced Tau burden concomitant with attenuated neurodegeneration ascribed to the education of resident microglia. These results may suggest that despite the opposing results with regard to the effect of TREM2 knockout in experimental Tau-based model systems, receptor engagement and activation by Ab-T1 appears to possess beneficial effects with respect to the various mechanisms mediating Tau-driven neurodegeneration.

MAP2 caps tau fibrils and inhibits aggregation

Fibrils of the microtubule-associated protein tau are intimately linked to the pathology of Alzheimer's disease (AD) and related neurodegenerative disorders. A current paradigm for pathology spreading in the human brain is that short tau fibrils transfer between neurons and then recruit naive tau monomers onto their tips, perpetuating the fibrillar conformation with high fidelity and speed. Although it is known that the propagation could be modulated in a cell-specific manner and thereby contribute to phenotypic diversity, there is still limited understanding of how select molecules are involved in this process. MAP2 is a neuronal protein that shares significant sequence homology with the repeat-bearing amyloid core region of tau. There is discrepancy about MAP2's involvement in pathology and its relationship with tau fibrillization. Here, we employed the entire repeat regions of 3R and 4R MAP2, to investigate their modulatory role in tau fibrillization. We find that both proteins block the spontaneous and seeded aggregation of 4R tau, with 4R MAP2 being slightly more potent. The inhibition of tau seeding is observed invitro, in HEK293cells, and in AD brain extracts, underscoring its broader scope. MAP2 monomers specifically bind to the end of tau fibrils, preventing recruitment of further tau and MAP2 monomers onto the fibril tip. The findings uncover a new function for MAP2 as a tau fibril cap that could play a significant role in modulating tau propagation in disease and may hold promise as a potential intrinsic protein inhibitor.

Seizures exacerbate excitatory‐inhibitory imbalance and tau seeding effects in 5XFAD mice

AbstractBackgroundAlzheimer’s Disease (AD) neuropathology is largely driven by two pathological proteins, tau, and ß‐amyloid, both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Central to the progression of AD is the spread of tau along neuronal networks likely via neuronal activity. Our previous work suggests a bidirectional relationship between AD and epilepsy with seizures inducing AD pathology and vice versa (Gourmaud et al. Brain, 2021; awab268). Additionally, there is evidence of excitatory‐inhibitory (E:I) imbalance in AD reminiscent of E:I imbalances involved in epileptogenesis. Thus, we hypothesized that seizures can exacerbate E:I imbalance in AD models and that this enhanced hyperexcitability promotes the propagation of pathological tau.MethodWe utilized the Five times familial AD (5XFAD) model and an established pentylenetetrazol (PTZ) kindling method to induce seizures in these and WT littermates. To model pathological tau spread seen in AD, a cohort of animals also underwent intracerebral injection of human AD‐derived tau (AD‐tau) into the hippocampus and overlying cortex prior to seizure induction. Western blots were performed for the Cl− transporters, K+‐ Cl−cotransporter 2 (KCC2) and Na+‐K+‐Cl− cotransporter 1 (NKCC1), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunits, GluA2 and GluA1, and GABAAR subunits α1 and α3, given their roles in E:I balance. AD‐tau injected mice were also examined by western blot for phospho‐tau AT8 [Ser202; Thr205] and phospho‐tau AT180 [Thr231] in sites proximal (hippocampus) and distal (frontal cortex) to injection site to determine the effects of seizures on tau propagation.ResultPTZ‐kindling enhanced the dysregulation of Cl‐ transporters, NKCC1 and KCC2 (p<0.05, n = 12‐19) and GluA2/GluA1 ratios (p<0.05, n = 12‐19) in 5XFAD mice, while 5XFAD mice showed decreased GABAARα1 (p<0.05, n = 12‐19). No significant changes were seen in the hippocampus for AT8 nor AT180, but seizure induction elevated AT8 levels in the frontal cortex across genotypes (p<0.05, n = 5‐9).ConclusionOur data suggest that seizures exacerbate E:I imbalance in 5XFAD mice and tau propagation in both WT and 5XFAD mice. Thus, drugs targeting mechanisms involved in E:I balance or controlling seizures with antiseizure medication shows therapeutic efficacy for AD patients with comorbid seizures.

Learning from anti‐tau antibody clinical trials using computer simulation of spatial tau propagation

AbstractBackgroundBased on the tau spreading hypothesis, anti‐tau antibodies have been developed that can bind to and eliminate the misfolded tau protein during the short extracellular period. However, trials with tau antibodies have come up short in improving clinical outcome in Progressive Supranuclear Palsy (PSP) or Alzheimer’s Disease (AD). It is unclear whether the negative outcomes were due to insufficient target engagement and to what extent the change of tau CSF biomarkers reflected the brain pharmacodynamics.MethodA Quantitative Systems Pharmacology (QSP) computer platform of tau biology has been developed including tau species diversity and their respective concentration, neuronal activity‐dependent tau secretion, tau binding to membrane surface receptors HSPG and LRP1, tau‐antibody binding and subsequent internalization of tau at the synaptic cleft. This model is combined with a Physiology‐Based PharmacoKinetic (PBPK) model to derive brain target exposure of tau antibodies. In addition, a PBPK model is used to simulate the level of plasma and CSF biomarkers.ResultThe platform was calibrated with preclinical in‐vitro cellular assays and after injection of brain extract in Transgene mouse models and was further humanized using published data on seed‐competent tau from postmortem AD brain at different Braak stages. Combining the extracellular antibody exposure, the spatial dimensions and the dynamics of tau secretion, diffusion and binding to the membrane surface receptors, the model suggests that a very limited fraction (10‐20%) of misfolded tau protein can be captured by antibodies and cleared. Even less reduction (5‐10%) is predicted for Progressive Supranuclear Palsy due to the higher affinity of PSP‐4R tau for membrane surface receptors. The reductions in misfolded tau protein are greatest in earlier stages of the disease. With regard to epitope selection, we identify conditions where high specificity (i.e. monomeric vs misfolded tau) is superior to high sensitivity (affinity).ConclusionAdvanced Quantitative Systems Pharmacology computer modeling combining drug exposure dynamics with mechanistic modeling allows to (1) generate testable hypotheses for the outcomes of current therapeutic interventions, (2) support improved clinical trial designs in terms of dosing, patient selection, background amyloid therapy and disease stage and (3) ultimately prioritize targets for addressing tau pathology.

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.

APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology.

Alzheimer's disease (AD), as the most common type of dementia, has two pathological hallmarks, extracellular senile plaques composed of β-amyloid peptides and intracellular neurofibrillary tangles containing phosphorylated-tau protein. Amyloid precursor protein (APP) and tau each play central roles in AD, although how APP and tau interact and synergize in the disease process is largely unknown. Here, we showed that soluble tau interacts with the N-terminal of APP in vitro in cell-free and cell culture systems, which can be further confirmed in vivo in the brain of 3XTg-AD mouse. In addition, APP is involved in the cellular uptake of tau through endocytosis. APP knockdown or N-terminal APP-specific antagonist 6KApoEp can prevent tau uptake in vitro, resulting in an extracellular tau accumulation in cultured neuronal cells. Interestingly, in APP/PS1 transgenic mouse brain, the overexpression of APP exacerbated tau propagation. Moreover, in the human tau transgenic mouse brain, overexpression of APP promotes tau phosphorylation, which is significantly remediated by 6KapoEp. All these results demonstrate the important role of APP in the tauopathy of AD. Targeting the pathological interaction of N-terminal APP with tau may provide an important therapeutic strategy for AD.

Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models.

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy.

Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model.

The tauopathy of Alzheimer's disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3-4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD.

Initial levels of β-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer’s disease

BackgroundTo better assist with the design of future clinical trials for Alzheimer’s disease (AD) and aid in our understanding of the disease’s symptomatology, it is essential to clarify what roles β-amyloid (Aβ) plaques and tau tangles play in longitudinal tau accumulation inside and outside the medial temporal lobe (MTL) as well as how age, sex, apolipoprotein E (APOE) ε4 (APOE-ε4), and Klotho-VS heterozygosity (KL-VShet) modulate these relationships.MethodsWe divided the 325 Aβ PET-positive (A+) participants into two groups, A+/T− (N = 143) and A+/T+ (N = 182), based on the threshold (1.25) of the temporal meta-ROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We then compared the baseline and slopes of A+/T− and A+/T+ individuals’ Aβ plaques and temporal meta-ROI tau tangles with those of A−/T− cognitively unimpaired individuals (N = 162) without neurodegeneration. In addition, we looked into how baseline Aβ and tau may predict longitudinal tau increases and how age, sex, APOE-ε4, and KL-VShet affect these associations.ResultsIn entorhinal, amygdala, and parahippocampal (early tau-deposited regions of temporal meta-ROI), we found that baseline Aβ and tau deposition were positively linked to more rapid tau increases in A+/T− participants. However, in A+/T+ individuals, the longitudinal tau accumulation in fusiform, inferior temporal, and middle temporal cortices (late tau-deposited regions of temporal meta-ROI) was primarily predicted by the level of tau tangles. Furthermore, compared to older participants (age ≥ 65), younger individuals (age < 65) exhibited faster Aβ-dependent but slower tau-related tau accumulations. Additionally, compared to the KL-VShet− group, KL-VShet+ individuals showed a significantly lower rate of tau accumulation associated with baseline entorhinal tau in fusiform and inferior temporal regions.ConclusionThese findings offer novel perspectives to the design of AD clinical trials and aid in understanding the tau accumulation inside and outside MTL in AD. In particular, decreasing Aβ plaques might be adequate for A+/T− persons but may not be sufficient for A+/T+ individuals in preventing tau propagation and subsequent downstream pathological changes associated with tau.

Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains

The speed and scope of cognitive deterioration in Alzheimer's disease is highly associated with the advancement of tau neurofibrillary lesions across brain networks. We tested whether the rate of tau propagation is a heritable disease trait in a large, well-characterized cohort of genetically divergent mouse strains. Using an AAV-based model system, P301L-mutant human tau (hTau) was introduced into the entorhinal cortex of mice derived from 18 distinct lines. The extent of tau propagation was measured by distinguishing hTau-producing cells from neurons that were recipients of tau transfer. Heritability calculation revealed that 43% of the variability in tau spread was due to genetic variants segregating across background strains. Strain differences in glial markers were also observed, but did not correlate with tau propagation. Identifying unique genetic variants that influence the progression of pathological tau may uncover novel molecular targets to prevent or slow the pace of tau spread and cognitive decline.

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

Dietary phytochemicals: As a potential natural source for treatment of Alzheimer's Disease

Alzheimer's disease (AD) is a common neurodegenerative disease, which seriously impairs human health and life. At present, scientists have proposed more than a dozen hypotheses about the pathogenesis of AD, including the tau propagation hypothesis. However, the exact ultimate pathogenic factor of AD remains unknown. Based on the current hypotheses, some anti-AD drugs (e.g., donepezil and Ketamine) have been developed and used in clinical treatment, which fall into two main categories, acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists, the former representative drug is donepezil, and the latter representative drug is memantine. Since these drugs have undesirable side effects, it is necessary to find safer alternatives for AD treatment. Interestingly, dietary phytochemicals have the advantages of wide source, safety, and high biological activity, which is the natural route for screening anti-AD drugs. In this study, several representatives’ dietary phytochemicals with anti-AD effect, including resveratrol, lycopene, gallic acid, berberine, ginsenoside Rg1, pseudoginsenoside-F11, ginsenoside Rh2, artemisinin, and torularhodin were selected from the published data over the last 10 years and their potential molecular mechanisms and clinical applications reviewed in the treatment of AD.

The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models

The prion-like transsynaptic propagation of misfolded tau along the brain’s connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological “milieu” in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players. However, the effects of these modulators remain unquantified. Here, we present Nexopathy in silico (“Nexis”), a quantitative model of tau progression augmenting earlier models by including parameters of pathology propagation defined by the molecular modulators of connectome-based spread. Our Nexis:microglia model provides the first quantitative characterization of this effect on the whole brain by expanding previous models of neuropathology progression by incorporating microglial influence. We show that Trem2, but not microglial homeostasis genes, significantly improved the model’s predictive power. Trem2 appears to reduce tau accumulation rate while increasing its interregional spread from the hippocampal seed area, causing higher tau burden in the striatum, pallidum, and contralateral hippocampus. Nexis provides an improved understanding and quantification of microglial contribution to tau propagation and can be flexibly modified to include other modulators of progressive neurodegeneration.

Baseline β‐amyloid and tau predict longitudinal tau accumulation at different stages of Alzheimer’s disease

AbstractBackgroundPrevious literatures suggest that β‐amyloid (Aβ) plaques, initial tau levels, age and Klotho‐VS heterozygosity (KL‐VShet) may be related to longitudinal tau accumulation in Alzheimer’s disease (AD), but it is still not fully understood how they predict tau replication in medial temporal cortex and propagations from the medial temporal lobe to inferior/middle temporal cortices at different stages of AD.MethodWe classified 325 Aβ PET positive (A+) ADNI participants into 143 A+/T‐and 182 A+/T+ according to the threshold (≥1.25) of Temporal‐metaROI 18F‐flortaucipir (FTP) standardized uptake value ratio (SUVR). Besides, 162 A‐/T‐ cognitive unimpaired participants without evidence of neurodegeneration were included as the reference group (Ref). We compared baseline and slopes of Aβ Centiloids and FTP SUVRs in 6 regions within Temporal‐metaROI with the Ref, and also investigated the prediction of longitudinal FTP SUVR changes by baseline Aβ Centiloids and FTP SUVRs in A+/T‐ and A+/T+ groups. Furthermore, we determined how age (Age&lt;65 and Age≥65 years) and KL‐VShet haplotype (KL‐VShet+ and KL‐VShet‐) affect these associations.ResultA+/T‐ showed significantly or marginally higher tau and faster tau increases in amygdala, entorhinal and parahippocampus than the Ref (Figure 1). Both baseline Aβ and entorhinal tau predicted faster rates of FTP SUVR increases in amygdala, entorhinal and parahippocampus in A+/T‐. While entorhinal tau predicted faster FTP SUVR increases in all the cortical regions within Temporal‐metaROI in A+/T+, baseline Aβ predicted faster FTP SUVR increases in fusiform, inferior and middle temporal regions (Figure 2). Additionally, younger ages showed faster baseline Aβ‐related whereas older ages had more tau‐related longitudinal FTP SUVR increases in fusiform and inferior temporal regions (Figure 3). KL‐VShet+ individuals exhibited attenuated entorhinal tau‐related FTP SUVR increases in fusiform and inferior temporal regions than the KL‐VShet‐ individuals (Figure 4).ConclusionAβ plaques and initial tau tangles may play different roles in tau replication and propagation in A+/T‐ and A+/T+ individuals, and may interact differently with age at prediction longitudinal tau accumulation. KL‐VShet may attenuated tau accumulation via modulating entorhinal tau‐related tau propagation. These findings may provide novel insights into understanding how tau tangles replicate and propagate in Temporal‐metaROI region at different stages of AD.