Pathological Tau Protein Research Articles

Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins.

Noradrenaline (NA) depletion occurs in Alzheimer's disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer's disease.

Recent studies have demonstrated that neuroplasticity, such as synaptic plasticity and neurogenesis, exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer's disease. Hence, promoting neuroplasticity may represent an effective strategy with which Alzheimer's disease can be alleviated. Due to their significant ability to self-renew, differentiate, and migrate, neural stem cells play an essential role in reversing synaptic and neuronal damage, reducing the pathology of Alzheimer's disease, including amyloid-β, tau protein, and neuroinflammation, and secreting neurotrophic factors and growth factors that are related to plasticity. These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain. Consequently, neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer's disease and other neurodegenerative diseases. In this review, we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer's disease in the clinic.

From Association to Intervention: The Alzheimer's Disease-Associated Processes and Targets (ADAPT) Ontology.

Many putative causes and risk factors have been associated with outcomes in Alzheimer's disease (AD) but all attempts at disease-modifying treatment have failed to be clinically significant. Efforts to address this "association-intervention" mismatch have tended to focus on the novel design of interventions. Here, we instead deal with the notion of association in depth. We introduce the concept of disease-associated process (DAP) as a flexible concept that can unite different areas of study of AD from genetics to epidemiology to identify disease-modifying targets. We sort DAPs using three properties: specificity for AD, frequency in patients, and pathogenic intensity for dementia before using a literature review to apply these properties in three ways. Firstly, we describe and visualize known DAPs. Secondly, we exemplify qualitative specificity analysis with the DAPs of tau protein pathology and autophagy to reveal their differential implication in AD. Finally, we use DAP properties to define the terms "risk factor," "cause," and "biomarker." We show how DAPs fit into our collaborative disease ontology, the Alzheimer's Disease-Associated Processes and Targets (ADAPT) ontology. We argue that our theoretical system can serve as a democratic research forum, offering a more biologically adequate view of dementia than reductionist models. The ADAPT ontology is a tool that could help to ground debates around priority setting using objective criteria for the identifying of targets in AD. Further efforts are needed to address issues of how biomedical research into AD is prioritized and funded.

Effects of central administration of the human Tau protein on the Bdnf, Trkb, p75, Mapt, Bax and Bcl-2 genes expression in the mouse brain.

Alzheimer's disease is the most common form of dementia, affecting millions of people worldwide. Despite intensive work by many researchers, the mechanisms underlying Alzheimer's disease development have not yet been elucidated. Recently, more studies have been directed to the investigation of the processes leading to the formation of neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated Tau proteins. Pathological aggregation of this protein leads to the development of neurodegeneration associated with impaired neurogenesis and apoptosis. In the present study, the effects of central administration of aggregating human Tau protein on the expression of the Bdnf, Ntrk2, Ngfr, Mapt, Bax and Bcl-2 genes in the brain of C57Bl/6J mice were explored. It was found that five days after administration of the protein into the fourth lateral ventricle, significant changes occurred in the expression of the genes involved in apoptosis and neurogenesis regulation, e. g., a notable decrease in the mRNA level of the gene encoding the most important neurotrophic factor BDNF (brain-derived neurotrophic factor) was observed in the frontal cortex which could play an important role in neurodegeneration caused by pathological Tau protein aggregation. Central administration of the Tau protein did not affect the expression of the Ntrk2, Ngfr, Mapt, Bax and Bcl-2 genes in the frontal cortex and hippocampus. Concurrently, a significant decrease in the expression of the Mapt gene encoding endogenous mouse Tau protein was found in the cerebellum. However, no changes in the level or phosphorylation of the endogenous Tau protein were observed. Thus, central administration of aggregating human Tau protein decreases the expression of the Bdnf gene in the frontal cortex and the Mapt gene encoding endogenous mouse Tau protein in the cerebellum of C57Bl/6J mice.

Concomitant Neuronal Tau Deposition and FKBP52 Decrease Is an Early Feature of Different Human and Experimental Tauopathies.

Pathological tau proteins constitute neurofibrillary tangles that accumulate in tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and familial frontotemporal lobar degeneration (FTLD-Tau). We previously showed that the FKBP52 immunophilin interacts functionally with tau and strongly decreases in AD brain neurons in correlation with tau deposition. We also reported that FKBP52 co-localizes with autophagy-lysosomal markers and an early pathological tau isoform in AD neurons, suggesting its involvement in autophagic tau clearance. Our objective was to evaluate if differences in neuronal FKBP52 expression levels and subcellular localization might be detected in AD, PSP, familial FTLD-Tau, and in the hTau-P301 S mouse model compared to controls. Cell by cell immunohistofluorescence analyses and quantification of FKBP52 were performed on postmortem brain samples of some human tauopathies and on hTau-P301 S mice spinal cords. We describe a similar FKBP52 decrease and its localization with early pathological tau forms in the neuronal autophagy-lysosomal pathway in various tauopathies and hTau-P301 S mice. We find that FKBP52 decreases early during the pathologic process as it occurs in rare neurons with tau deposits in the marginally affected frontal cortex region of AD Braak IV brains and in the spinal cord of symptomless 1-month-old hTau-P301 S mice. As FKBP52 plays a significant role in cellular signaling and conceivably in tau clearance, our data support the idea that the prevention of FKBP52 decrease or the restoration of its normal expression at early pathologic stages might represent a new potential therapeutic approach in tauopathies including AD, familial FTLD-Tau, and PSP.

Human amygdala involvement in Alzheimer's disease revealed by stereological and dia-PASEF analysis.

Alzheimer's disease (AD) is characterized by the accumulation of pathological amyloid-β (Aβ) and Tau proteins. According to the prion-like hypothesis, both proteins can seed and disseminate through brain regions through neural connections and glial cells. The amygdaloid complex (AC) is involved early in the disease, and its widespread connections with other brain regions indicate that it is a hub for propagating pathology. To characterize changes in the AC as well as the involvement of neuronal and glial cells in AD, a combined stereological and proteomic analysis was performed in non-Alzheimer's disease and AD human samples. The synaptic alterations identified by proteomic data analysis could be related to the volume reduction observed in AD by the Cavalieri probe without neuronal loss. The pathological markers appeared in a gradient pattern with the medial region (cortical nucleus, Co) being more affected than lateral regions, suggesting the relevance of connections in the distribution of the pathology among different brain regions. Generalized astrogliosis was observed in every AC nucleus, likely related to deposits of pathological proteins. Astrocytes might mediate phagocytic microglial activation, whereas microglia might play a dual role since protective and toxic phenotypes have been described. These results highlight the potential participation of the amygdala in the disease spreading from/to olfactory areas, the temporal lobe and beyond. Proteomic data are available via ProteomeXchange with identifier PXD038322.

A Candidate microRNA Profile for Early Diagnosis of Sporadic Alzheimer's Disease.

Late-onset or sporadic Alzheimer's disease (sAD) is a neurodegenerative disease leading to cognitive impairment and memory loss. The underlying pathological changes take place several years prior to the appearance of the first clinical symptoms, however, the early diagnosis of sAD remains obscure. To identify changes in circulating microRNA (miR) expression in an effort to detect early biomarkers of underlying sAD pathology. A set of candidate miRs, earlier detected in biofluids from subjects at early stage of sAD, was linked to the proposed tau-driven adverse outcome pathway for memory loss. The relative expression of the selected miRs in serum of 12 cases (mild cognitive impairment, MCI) and 27 cognitively normal subjects, recruited within the ongoing Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) study, was measured by RT-qPCR. Data on the protein levels of amyloid-β (Aβ42) and total/phosphorylated tau (t-tau/p-tau), in cerebrospinal fluid (CSF), and the cognitive z-scores of the participants were also retrieved. Each doubling in relative expression of 13 miRs in serum changed the odds of either having MCI (versus control), or having pathological Aβ42 or pathological Aβ42 and tau (versus normal) proteins in their CSF, or was associated with the global composite z-score. These candidate human circulating miRs may be of great importance in early diagnosis of sAD. There is an urgent need for confirming these proposed early predictive biomarkers for sAD, contributing not only to societal but also to economic benefits.

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimer's Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.

A multi-scale model explains oscillatory slowing and neuronal hyperactivity in Alzheimer’s disease

Alzheimer's disease is the most common cause of dementia and is linked to the spreading of pathological amyloid-β and tau proteins throughout the brain. Recent studies have highlighted stark differences in how amyloid-β and tau affect neurons at the cellular scale. On a larger scale, Alzheimer's patients are observed to undergo a period of early-stage neuronal hyperactivation followed by neurodegeneration and frequency slowing of neuronal oscillations. Herein, we model the spreading of both amyloid-β and tau across a human connectome and investigate how the neuronal dynamics are affected by disease progression. By including the effects of both amyloid-β and tau pathology, we find that our model explains AD-related frequency slowing, early-stage hyperactivation and late-stage hypoactivation. By testing different hypotheses, we show that hyperactivation and frequency slowing are not due to the topological interactions between different regions but are mostly the result of local neurotoxicity induced by amyloid-β and tau protein.

Single domain antibody‐based non‐invasive in vivo imaging of tau pathology

AbstractBackgroundNumerous studies have shown that the extent of pathological tau protein in the brain correlates strongly with the severity of Alzheimer’s dementia at the time of death, and similar association with functional phenotypes have been seen in other tauopathies. In recent years, several dye‐based imaging probes with selectivity for tau aggregates have been developed. However, all are β‐sheet binders with varying affinity for different amyloids, and thereby lack specificity for tau lesions. In contrast, single domain antibodies (sdAbs) are specific for their target and because of their small size have much greater access into the brain than standard whole antibodies.MethodTo examine sdAbs’ suitability as non‐invasive in vivo imaging probes for tauopathies, we immunized a llama with a full‐length recombinant tau protein followed by boosters with human brain‐derived pathological tau proteins. Phage display libraries were generated from its peripheral blood mononuclear cells and screened for binding to tau proteins using various assays, resulting in a prototype sdAb deemed promising for in vivo imaging. Subsequently, this anti‐tau sdAb was labeled with a near‐infrared tag (680 nm), and injected intravenously in tauopathy and control mice, followed by imaging using an In Vivo Imaging System (IVIS). After the imaging, brains were extracted for tissue analysis.ResultIntravenous injection of labeled sdAb resulted in a strong in vivo brain signal detected through the intact head in two different models of transgenic tauopathy mice, but not in wild‐type or transgenic α‐synucleinopathy mice. Importantly, the in vivo brain signal correlated strongly with insoluble (r = 0.9839, p < 0.0001) and soluble (human tau (CP27) and phospho‐tau (PHF1): r = 0.9603 and 0.9459, p < 0.0001) tau protein within the brain. Furthermore, postmortem analysis revealed extensive co‐localization of the sdAb imaging probe with tau aggregates within neurons in the endosomal‐lysosomal system, indicating their interaction in these degradation pathways.ConclusionOverall, this specific sdAb imaging ligand has great potential as an in vivo diagnostic marker for Alzheimer's disease and related tauopathies, and sdAb‐based imaging may be applicable to a variety of protein conformational disorders.

Brain Derived Biologically Relevant Tau Oligomers

AbstractBackgroundNeurodegenerative Tauopathies, including Alzheimer’s disease (AD), are characterized by the appearance of extracellular lesions composed of aggregated and post‐translationally modified tau proteins. The resulting tau pathology is an established marker for differential disease diagnosis and staging, a surrogate marker for neurodegeneration, a potential vector for disease propagation, and a source of toxicity in biological models. In comparison to the well‐established methods for isolation/preparation and biochemical and structural characterization of stable tau filaments from tauopathy brain, the characterization of smaller and much dynamic oligomeric tau aggregates has not been investigated to the same degree. As a result, tau oligomers that may associate most closely with disease propagation and toxicity as suggested by a large body of research, are not fully established.MethodHerein, we leverage our well‐optimized brain‐derived tau oligomers (BDTOs) from well‐vetted human tauopathy cases of AD, progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB). In addition to our rigorous biochemical characterization of the BDTOs by immunological probing, and structural characterization by proteolysis and microscopic analyses, we have optimized Fluorescent Amyloid Multi Emission Spectra (FLAMES) microscopy for cataloging and comparing tau conformational variants across a wide range of samples, from brain tissue sections and BDTOs to in vitro aggregated tau assemblies. For selective immunodetection of the BDTOs, we have used our novel four fully sequenced and epitope mapped Tau Oligomer Monoclonal Antibodies (TOMAs), which recognize non‐continuous sequences on tau. Furthermore, the bioactivity of the BDTOs was assessed by evaluating their seeding propensity in biosensor cells and primary cortical neurons from tauopathy mice and their effects on synaptic function by electrophysiological studies.ResultWe observed that the BDTOs differed in their immunological properties, morphology, and sensibility/stability to proteolysis. The BDTOs were distinguished based on FLAMES spectral signature. Distinct seeding propensity and impairment of long‐term potentiation (LTP) indicated their differences in bioactivity as well.ConclusionOur thorough investigation/characterization of biologically active disease‐relevant tau oligomers will provide new opportunities to diagnose and evaluate therapeutics beyond the current capabilities for AD and related tauopathies by developing specific tau aggregation inhibitors and/or diagnostic probes for pathological tau protein.

In Vitro Amplification of Pathogenic Tau Seeds from Neurodegenerative Disease Patient Brains.

Aggregated microtubule-associated protein tau (tau) is the hallmark lesion of a group of neurodegenerative diseases, termed tauopathies. Normal endogenous tau is highly soluble and intrinsically disordered when it is not bound to microtubules. Pathological tau proteins are aggregates of bioactive filaments capable of inducing their normal counterparts into pathological conformations that are human tauopathy dependent. Taking advantage of this feature, we established an in vitro seeding reaction to amplify faithfully human-derived tau strains. This approach allows us to expand the quantity and improve the quality of pathogenic tau strains derived from human patient postmortem brains and to further understand tau pathogenesis in models of tauopathy. Here, we describe the approach to generate human pathogenic tau using human-derived tau seeds and recombinant human tau in vitro.

Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models

Neurofibrillary tangles (NFT), a neuronal lesion found in Alzheimer's disease (AD), are composed of fibrillary aggregates of modified forms of tau proteins. The propagation of NFT follows neuroanatomical pathways suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau in a prion-like manner. Moreover, the intracerebral injection of pathological tau from AD brains induces the seeding of normal tau in mouse brain. Creutzfeldt-Jacob disease has been transmitted after ocular transplants of cornea or sclera and the scrapie agent can spread across the retino-tectal pathway after intraocular injection of scrapie mouse brain homogenates. In AD, a tau pathology has been detected in the retina. To investigate the potential risk of tau pathology transmission during eye surgery using AD tissue material, we have analysed the development of tau pathology in the visual pathway of mice models expressing murine tau, wild-type or mutant human tau after intraocular injection of pathological tau proteins from AD brains. Although these pathological tau proteins were internalized in retinal ganglion cells, they did not induce aggregation of endogenous tau nor propagation of a tau pathology in the retino-tectal pathway after a 6-month incubation period. These results suggest that retinal ganglion cells exhibit a resistance to develop a tau pathology, and that eye surgery is not a major iatrogenic risk of transmission of tau pathology, contrary to what has been observed for transmission of infectious prions in prion diseases.

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity.

SummaryBackgroundEleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results.MethodsWe selected two single domain antibodies (sdAbs) derived from a llama immunized with tau proteins and utilized them to generate an array of Fc-(sdAb)2 subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice.FindingsUnmodified sdAbs were non-toxic, blocked tau toxicity and promoted tau clearance. However, the efficacy/safety profile of their Fc-(sdAb)2 subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo.InterpretationThese findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it.FundingFunding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051).

Pathological changes induced by Alzheimer’s brain inoculation in amyloid-beta plaque-bearing mice

Alzheimer's disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-β (Aβ) plaques and intracellular tau pathology that spread in the brain. Three types of tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding Aβ deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in Aβ plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the present study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused into the hippocampus of Aβ plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as Aβ plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. ADbe inoculation produced the following effects: (i) memory deficit; (ii) increased Aβ plaque deposition in proximity to the inoculation site; (iii) tau pathology induction; (iv) appearance of neuropil threads and neurofibrillary tangles next to the inoculation site with a spreading to connected regions. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe-inoculated animals but ADbe inoculation increased the severity close to and at distance of the inoculation site. (v) Finally, ADbe inoculation reduced synaptic density in the vicinity to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not to other tau lesions or Aβ lesions, suggesting that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load.Graphical abstract

Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy.

IntroductionThe typical symptoms of Alzheimer’s disease (AD) are cognitive impairment, disrupted spatial orientation, behavioral and psychiatric abnormalities, and later motor deficits. Neuropathologically, AD is characterized by deposits of pathological forms of endogenous proteins – amyloid-β, and neurofibrillary tau protein pathology. The latter closely correlates with brain atrophy and clinical impairment. Pharmacological therapies for these pathologies are largely absent, raising the question whether non-pharmacological interventions could be efficacious. Environmental factors can play a role in the manifestation of AD. It is unknown whether enriched environment (EE) can ameliorate the propagation of protein aggregates or their toxic components.MethodsWe injected insoluble tau extracts from human brains with AD (600 or 900 ng per animal) into hippocampi of SHR72 transgenic rats that express non-mutated truncated human tau 151-391/4R, but usually do not develop hippocampal tangles. The rats had either standard housing, or could access an EE 5×/week for 3 months. Behavioral analysis included the Morris Water Maze (MWM). Histological analysis was used to assess the propagation of tau pathology.ResultsAnimals exposed to EE performed better in the MWM (spatial acquisition duration and total distance, probe test); unexposed animals improved over the course of acquisition trials, but their mean performance remained below that of the EE group. Enriched environment abrogated tau propagation and hippocampal tangle formation in the 600 ng group; in the 900 ng group, tangle formation was ∼10-fold of the 600 ng group, and unaffected by EE.ConclusionEven a small difference in the amount of injected human AD tau can cause a pronounced difference in the number of resulting tangles. EE leads to a noticeably better spatial navigation performance of tau-injected animals. Furthermore, EE seems to be able to slow down tau pathology progression, indicating the possible utility of similar interventions in early stages of AD where tangle loads are still low.

Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice

ABSTRACT Neurodegenerative diseases involving pathological tau protein aggregation are collectively known as tauopathies and include Alzheimer’s disease and Pick’s disease. Recent studies show that the intake of tryptophan-tyrosine (Trp-Tyr)-related β-lactopeptides, including β-lactolin, attenuates cognitive decline in the elderly and prevents the amyloid pathology in mouse models of Alzheimer’s disease. However, the effects of Trp-Tyr-related β-lactopeptides on tau-related pathology have not been investigated. In the present study, we examined the effects of Trp-Tyr dipeptide intake on tauopathy in PS19 transgenic mice, a well-established tauopathy model. Intake of Trp-Tyr dipeptide improved the behavioral deficits observed in the open field test, prevented tau phosphorylation, and increased the dopamine turnover and synaptophysin expression in the frontal cortex. Levels of short-chain fatty acids in the cecum were lower in PS19 mice than those in wild-type mice and were increased by treatment with Trp-Tyr dipeptide. In addition, intake of Trp-Tyr dipeptide extended the lifespan of PS19 mice. These findings suggest that the intake of Trp-Tyr-related peptides improves tauopathy symptoms, resulting in improvements in behavioral deficits and longevity. Hence, the intake of Trp-Tyr-related peptides, including β-lactolin, may be beneficial for preventing dementia.

Role of Structural Polymorphisms of Tau Filaments in the Pathological Diversity of Tauopathies

Pathological tau protein accumulated in the brain of patients with tauopathies undergoes structural changes into amyloid-like filaments and forms the intracellular deposits that characterize the disease. Structural and biochemical classification of pathogenic tau extracted from patients' brains supports the hypothesis that structural polymorphisms of tau filaments occur in the brain. Additionally, disease-specific tau pathologies are recapitulated in in vitro and in vivo experimental models that mimic tau aggregation and dissemination and indicate that conformation of tau filaments is a key contributor to the pathological diversity in tauopathy. In this review, we describe the structural and biochemical features of pathological tau extracted from the brain of patients with tauopathies and discuss the possible mechanisms underlying amplification and dissemination of pathological tau in the brain.

The association of enlarged perivascular space with microglia-related inflammation and Alzheimer's pathology in cognitively normal elderly

BackgroundGlymphatic dysfunction may contribute to the accumulation of Alzheimer's disease (AD) pathologies. Conversely, AD pathologic change might also cause neuroinflammation and aggravate glymphatic dysfunction, forming a loop that accelerates AD progression. In vivo validations are needed to confirm their relationships. MethodsIn this study, we included 144 cognitively normal participants with AD pathological biomarker data (baseline CSF Aβ1–42, T-Tau, P-Tau181; plasma P-Tau181 at baseline and at least one follow-up) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Each subject had completed structural MRI scans. Among them, 117 subjects have available neuroinflammatory biomarker (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and 123 subjects have completed two times [18F]-florbetapir PET. The enlarged PVS (EPVS) visual rating scores in basal ganglia (BG) and centrum semiovale (CS) were assessed on T1-weighted images to reflect glymphatic dysfunction. Intracranial volume and white matter hyperintensities (WMH) volume were also calculated for further analysis. We performed stepwise linear regression models and mediation analyses to estimate the association between EPVS severity, sTREM2, and AD biomarkers. ResultsCS-EPVS degree was associated with CSF sTREM2, annual change of plasma P-tau181 and total WMH volume, whereas BG-EPVS severity was associated with age, gender and intracranial volume. The sTREM2 mediated the association between CSF P-tau181 and CS-EPVS. ConclusionImpaired glymphatic dysfunction could contribute to the accumulation of pathological tau protein. The association between tauopathy and glymphatic dysfunction was mediated by the microglia inflammatory process. These findings may provide evidence for novel treatment strategies of anti-neuroinflammation therapy in the early stage.

Spinal Cord Injury Causes Prominent Tau Pathology Associated with Brain Post-Injury Sequela.

Spinal cord injury (SCI) can result in significant neurological impairment and functional and cognitive deficits. It is well established that SCI results in focal neurodegeneration that gradually spreads to other cord areas. On the other hand, traumatic brain injury (TBI) is strongly associated with tau protein pathology and neurodegeneration that can spread in areas throughout the brain. Tau is a microtubule-associated protein abundant in neurons and whose abnormalities result in neuronal cell death. While SCI and TBI have been extensively studied, there is limited research on the relationship between SCI and brain tau pathology. As a result, in this study, we examined tau pathology in spinal cord and brain samples obtained from severe SCI mouse models at various time points. The effects of severe SCI on locomotor function, spatial memory, anxiety/risk-taking behavior were investigated. Immunostaining and immunoblotting confirmed a progressive increase in tau pathology in the spinal cord and brain areas. Moreover, we used electron microscopy to examine brain samples and observed disrupted mitochondria and microtubule structure following SCI. SCI resulted in motor dysfunction, memory impairment, and abnormal risk-taking behavior. Notably, eliminating pathogenic cis P-tau via systemic administration of appropriate monoclonal antibodies restored SCI's pathological and functional consequences. Thus, our findings suggest that SCI causes severe tauopathy that spreads to brain areas, indicating brain dysfunction. Additionally, tau immunotherapy with an anti-cis P-tau antibody could suppress pathogenic outcomes in SCI mouse models, with significant clinical implications for SCI patients. SCI induces profound pathogenic cis p-tau, which diffuses into the brain through CSF, resulting in brain neurodegeneration and cognitive decline.