Tau Proteinopathies Research Articles

Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

Association of in vivo retention of [18f] flortaucipir pet with tau neuropathology in corresponding brain regions

[18F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer’s disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative post-mortem tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [18F]flortaucipir PET uptake and quantitative post-mortem tau pathology in corresponding brain regions from the AVID A16 end-of-life study (n = 63). All participants underwent [18F]flortaucipir PET scans prior to death, followed by a detailed post-mortem neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [18F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [18F]flortaucipir specificity and level of detection for tau pathology, correlations between [18F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [18F]flortaucipir SUVR and post-mortem tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p < 0.0001 for all). The detection threshold of [18F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [18F]flortaucipir SUVRs and post-mortem tau pathology in individuals with possible PART. Further, there was no correlation observed between [18F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range = – 0.16–0.12; p = 0.48–0.61) or TDP-43 stage (rho-range = – 0.10 to – 0.30; p = 0.18–0.65). In conclusion, our in vivo vs post-mortem study shows that the in vivo [18F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.

Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies

Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages.

Study of the neuroprotective properties of the heteroreceptor EPOR/CD131 agonist of peptide structure in tau-proteinopathy modeling

Introduction: Tau proteinopathy is a pathology associated with the activation of post-translational modifications and interactions of pathophysiological cascades of neuroinflammation with hyperphosphorylation of Tau aggregates. Therefore, preference is given to agents that have properties in reducing or slowing down the processes of neuroinflammation and post-translational modifications in the brain. Materials and Methods: The study was conducted on male and female homozygous individuals of a transgenic murine line with overexpression of mutant human Tau gene (P301S) and a background wild mouse line C57Bl/6J. To assess the progression of Tau proteinopathy, behavioral tests were used at two control time points, and the last one measured the level of neuroinflammation markers and tau-proteinopathy. Results and Discussion: In the group of P301S mice treated with ARA-290, an improvement in the phenotypic picture of Tau proteinopathy was demonstrated compared with intact animals. In the Barnes circular maze test, mice showed a decrease in the total distance traveled and the latent time spent on the platform, which indicates a rapid entry into the shelter. In the O-shaped maze test, the group maintained a fairly high level of spontaneous exploratory behavior. In the vertical rod test, the animals recorded the best time indicators that they needed to turn and maintain balance compared to the intact group. A statistically significant decrease in the level of GSK-3β and an increase in CDK5 and PP2A were revealed, which indicates a dephosphorylating effect on Tau protein, as well as markers of neuroinflammation. NF-KB and TNF-α were significantly reduced by 57% and 32%, respectively, compared to the intact group. Conclusion: In the model of transgenic P301S murine line with overexpression of the mutant human Tau gene, the peptide agonist of the EPOR/CD 131 heteroreceptor demonstrated neuroprotective properties, which were confirmed by indicators of behavioral tests and markers of neuroinflammation and tau-proteinopathy.

Developing Topics.

Alzheimer's disease (AD) is highly related to brain amyloid and tau deposition. PET images evaluate these patterns of amyloid and tau proteinopathy noninvasively. Tau PET is less familiar than amyloid PET to clinicians and researchers, it may occur inter- and intra-observer variability to determine abnormalities in visual rating. We purposed to find optimal thresholds of tau PET, compared with visual assessment, and suggest the most appropriate standard of tau PET assessment using the assist of automated quantitative analysis of PET. 101 participants were enrolled in tau (18F-flortaucipir), amyloid (18F-flutemetamol) PET, and a three-dimension T1-weighted MR image study. Each regional SUVR was calculated using SCALE PET version 1.2 (Neurophet Inc., Seoul, Republic of Korea.). Each regions-of-interest (ROI)-mean SUVR of reference region (whole cerebellum (CW) and cerebellar gray matter (CG)) and quantitative Tau PET positivity was compared with visual rating results of a nuclear medicine physician. We compared accuracy of tau PET positivity driven from 1) total Braak ROI, 2) a priori ROI, and 3) whole cerebral cortical mean SUVR above 1.65 (CW, CG) or 1.30 (CG). The highest accuracy was observed 0.832 with above 1.65 mean SUVR in a priori ROI using CG reference region. False negative (FN), where participants classified as negative with mean SUVR when visually positive (FN), was 26.7%. These FN participants were mostly identified as borderline patients who were categorized to Braak III/IV (3) or V/VI (24) in visual rating. All the participants classified as tau positive in the quantitative method were amyloid positive while 54.1% were in the tau negative group. Also, the patient group composed of AD and mild cognitive impairment (MCI) participants was 96.3% in positive, behalf 55.4% in negative group. Both visual rating and quantitative classification showed a significant difference between negative and positive groups (p <0.001). Visual assessment may provide more sensitive outcome than quantitative estimation, i.e., mean SUVR. Our quantitative methods of tau PET showed high accuracy with visual assessment in the regions of early Braak stage, i.e., Braak I/II/III/IV. In the future, there needed to develop more sensitive cutoff values or quantitative methods for tauopathy deposition observation.

CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer's Disease and Frontotemporal Dementias.

Alzheimer's disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aβ42 and Aβ40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ42/Aβ40 ratio was superior to Aβ42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. Aβ42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.

Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.

Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.

Nurr1 and Foxa2 Delivered by Adeno‐Associated Virus 9 Ameliorate the Pathologies and Symptoms of Alzheimer’s Disease Models

AbstractBackgroundSince conventional chemical drugs or proteins have not shown sufficient clinical benefits for cognitive impairments in Alzheimer’s disease (AD), we could try to develop novel therapeutic interventions for AD such as gene therapy. In this study, we evaluated a novel therapeutic modality of AAV9 vectors expressing Nurr1 and Foxa2 genes to treat AD symptoms and pathologies in animal disease models.MethodThe AAV9 vectors expression Nurr1 and Foxa2 were injected together into the hippocampi and lateral ventricles of two different AD models, such as 3x Transgenic (15‐18 months) and 5x Familial Alzheimer Disease (3 months) mice. We tested memory and cognitive functions, accumulation of amyloid β and Tau protein, inflammation and immune activity in the brain of AD models.ResultCombined transduction of AAV9‐Nurr1 and AAV9‐Foxa2 remarkably improved memory and cognitive functions of 3xTg mice in Y‐maze and water‐maze tests compared to vehicle‐treated group. In 5xFAD mice, Nurr1 and Foxa2 co‐expression effectively rescued memory deficits in the passive avoidance and novel object recognition tests, and made the impaired long‐term potentiation restore to wild‐type level.We intensively investigated modes of action of therapeutic genes. Nurr1 and Foxa2 co‐expression significantly decreased Aβ deposits in the brain of 3xTg and 5xFAD mice. Subsequent transcriptome analyses revealed that two genes up‐regulated the expression of Aβ‐degrading enzymes.Tau plaque formation was also reduced in therapeutic gene‐treated 3xTg group, accompanied by deceased phosphorylation of Tau through inflammasome suppression and GSK‐3β inactivation.Nurr1 and Foxa2 ameliorated neuro‐toxic environment by correcting pathologic inflammatory glial phenotypes. They decreased the expression of inflammatory cytokines, chemokines, and complements through inactivation of NF‐κB pathway, while up‐regulated expression of neurotrophic factors.Along with increased expression of pre‐ and post‐synaptic markers, synaptic density in the hippocampal CA1 was greater in the 3xTg mice treated with therapeutic genes than control.ConclusionA series of functional, histologic and transcriptome analyses revealed that the co‐expression of Nurr1 and Foxa2 attenuated AD‐associated Aβ and Tau proteinopathy, neuro‐inflammation, immune activation, and synaptic loss in multiple in vitro and in vivo AD models. These findings collectively indicate intra‐cranial delivery of Nurr1 and Foxa2 using AAV9 could be an efficient disease‐modifying therapy for AD.

Amyloid and tau pathologies associate with distinct aspects of the inflammatory cascade

AbstractBackgroundInflammation has long been pointed out as a key feature in Alzheimer’s disease (AD). However, the heterogeneity of AD pathology might trigger different aspects of the immune response. Here, we aimed to study the association of the newly proposed concept of inflammatory composite indexes with Aβ and tau pathologies across the aging and AD spectra. We hypothesize that distinct inflammatory pathways are associated with the different hallmarks of AD.MethodA panel of 92 inflammation‐related markers was measured in the CSF of 60 individuals (35 cognitively unimpaired and 25 cognitively impaired) from the McGill TRIAD cohort. These 92 proteins were clustered by ontogenetic similarity and physical interaction using STRING. A z‐scored composite value representing each cluster was created for each individual. Individuals were classified as Aβ‐ and tau‐positive using global [18F]AZD4694 and temporal meta‐ROI [18F]MK6240 PET, respectively. Linear regressions (corrected by diagnosis, age, sex, and APOEɛ4 status) and receiver operating characteristic (ROC) analyses evaluated clusters’ performance.ResultOf the six clusters identified in our protein network analysis, three positively correlated with global Aβ‐PET (C4,C5, and C6) and three with meta‐ROI tau PET (C2,C4, and C5;Fig.1). However, controlling for Aβ PET, tau PET was only associated with C2, indicating that the association with the other two clusters (C4 and C5) was dependent of Aβ pathology. The cluster exclusively associated with tau (C2), represents tumor necrosis factor‐mediated signaling pathways. On the other hand, C6, related to the stimulation of interferon‐gamma production, and C5, related to glial cell‐derived neurotrophic receptor binding, are exclusively associated with Aβ. ROC analysis showed that all clusters presented a better performance predicting Aβ‐PET positivity than tau‐PET positivity (Fig.2A,B). Additionally, overall the clusters showed a better performance than sTREM2, a classical inflammatory biomarker.ConclusionOur novel clustering approach supports that Aβ and tau proteinopathies are associated with distinct aspects of the inflammatory cascade. Our results suggest that a composite of inflammatory proteins better identifies AD pathology than a single marker. Finally, this suggested cluster approach helps to understand the inflammatory response to Aβ and tau and can uncover inflammation‐related AD pathways.

Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology.

There is a compelling need to develop disease-modifying therapies for Alzheimer's disease (AD), the most common neuro-degenerative disorder. Together with recent progress in vector development for efficiently targeting the central nervous system, gene therapy has been suggested as a potential therapeutic modality to overcome the limited delivery of conventional types of drugs to and within the damaged brain. In addition, given increasing evidence of the strong link between glia and AD pathophysiology, therapeutic targets have been moving toward those addressing glial cell pathology. Nurr1 and Foxa2 are transcription/epigenetic regulators that have been reported to cooperatively regulate inflammatory and neurotrophic response in glial cells. In this study, we tested the therapeutic potential of Nurr1 and Foxa2 gene delivery to treat AD symptoms and pathologies. A series of functional, histologic, and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid β and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple in vitro and in vivo AD models. Intra-cranial delivery of Nurr1 and Foxa2 genes using adeno-associated virus (AAV) serotype 9 improved the memory and cognitive function of AD model mice. The therapeutic benefits of gene delivery were attained mainly by correcting pathologic glial function. These findings collectively indicate that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.

Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy.

Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)-a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases-in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels regardless of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice expressing P301S mutant tau, whereas P301S mice lacking UBQLN2 showed significantly reduced phosphorylated tau. Further studies support the view that an imbalance of UBQLN2 perturbs ubiquitin-dependent PQC and autophagy. We conclude that changes in UBQLN2 levels, whether because of pathogenic mutations or secondary to disease states, such as tauopathy, contribute to proteostatic imbalances that exacerbate neurodegeneration.SIGNIFICANCE STATEMENT We defined a role for the protein quality control protein Ubiquilin-2 (UBQLN2), in age-related neurodegenerative tauopathies. This group of disorders is characterized by the accumulation of tau protein aggregates, which differ when UBQLN2 levels are altered. Given the lack of effective disease-modifying therapies for tauopathies and the function of UBQLN2 in handling various disease-linked proteins, we explored the role of UBQLN2 in regulating tau. We found that UBQLN2 reduced tau levels in cell models but behaved differently in mouse brain, where it accelerated mutant tau pathology and tau-mediated toxicity. A better understanding of the diverse functions of regulatory proteins like UBQLN2 can elucidate some of the causative factors in neurodegenerative disease and outline new routes to therapeutic intervention.

Understanding the transcriptional (dys)regulation in progressive supranuclear palsy

Progressive Supranuclear Palsy (PSP) is an incurable, neurodegenerative parkinsonian disorder characterized by tau proteinopathy in multiple brain cell types. We previously reported global gene expression changes associated with neuropathologic endophenotypes in PSP. In this study, we expanded this work to brain RNA sequence (RNAseq) transcriptome data from two independent cohorts and assessed both bulk and analytically deconvoluted transcriptome integrated with other omics data from humans and mice to discover dysregulated genes and networks in PSP. Transcriptome was measured in 408 temporal cortex samples from two independent cohorts of PSP and control brains, all of which had quantitative neuropathology scores. Differentially expressed genes (DEG) were identified using both bulk and analytically deconvoluted transcriptome for each brain cell type. Weighted Gene Co-expression Network Analysis (WGCNA) was used to construct modules, which were annotated for enrichment of Gene Ontology terms and cell type markers. We sought validations using a multitude of complementary datasets, including PSP GWAS, eQTL, proteome data and tau transgenic mouse models. There were 22,560 genes detected in both cohorts of which 1,709 were significantly differentially expressed. Among the DEGs, 721 genes also had nominal associations with one or more neuropathology endophenotypes. Additionally, 104 of the bulk DEGs were also differentially expressed in one of the brain cell types, i.e. were cell-intrinsic DEGs (CI-DEGs). There were 23 co-expression network modules, 10 of which were enriched for brain cell type markers; 8 of these also demonstrated enrichment of CI-DEGs of the corresponding cell-type. Importantly, 3 of these 8 modules also associated with PSP diagnosis. The most significant modules were enriched for oligodendrocyte and astrocyte genes and CI-DEGs. Most notably, we identified one module with enrichment of oligodendrocyte gene markers that are likewise downregulated in PSP. This module was also enriched with myelin gene expression changes identified in oligodendrocyte CI-DEGs. The expression profile of PSP brain changes in a cell-specific manner. Astrocyte and oligodendrocyte gene expression appears most impacted in PSP. Our findings implicate novel genes and pathways which underlie disease risk and neuropathology in PSP and may serve as novel therapeutic and biomarker targets.

Conserved architecture of brain transcriptome changes between Alzheimer's disease and progressive supranuclear palsy in pathologically affected and unaffected regions.

Alzheimer's disease (AD) is a complex proteinopathy with abnormal accumulation of amyloid β and tau in which the temporal cortex (TCx) is severely affected. Progressive supranuclear palsy (PSP) is a primary tau proteinopathy. Neurodegeneration in the TCx is less severe in PSP than in AD. In contrast, the cerebellum (CER) is relatively spared from gross pathology especially in AD. To determine if there are shared molecular changes that occur in both AD and PSP and explore these in the context of neuropathological burden, we analyzed RNAseq data from post-mortem TCx and CER of AD and PSP patients, as well as controls without neurodegenerative disease. For each brain region, we performed differential gene expression analyses between AD and normal controls (ADvC), and between PSP and controls (PSPvC) using two linear regression models independently. The first model adjusted for sex, age, and technical variables, whereas the second model adjusted for cellular composition in addition to the variables included in the first. We performed comparative analysis (Pearson correlation) of the results between disease groups and brain regions. The slope and Pearson correlation between β coefficients of DEGs obtained from PSPvC and those from ADvC were highly significant for both TCx (slope=0.31, R2 =0.27, p<1.0E-10) and CER (slope=0.78, R2 =0.69, p<1.0E-10). The slope and correlation between the β coefficients increased with increasing significance of DEGs, approaching R2 =1 for DEGs with q<0.01. These observations held for both models. Comparison of β coefficients between TCx ADvC and CER ADvC, and between TCx PSPvC and CER PSPvC revealed similar trends. Enrichment analysis identified shared pathways implicated in both diseases. There is a striking correlation in the directionality and magnitude of significant gene expression changes in brain transcriptomes between AD and PSP and between the temporal and cerebellar cortices. These findings indicate conservation in transcriptomic alterations due to common proteinopathies or their downstream effects and demonstrate the widespread perturbations of systems in the whole brain in neurodegenerative diseases. This work highlights the presence of transcriptome changes in pathologically "unaffected" brain regions and identifies biological pathways that are ubiquitously altered across brain regions and distinct neurodegenerative diseases.

Supplementary File: Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Supplementary File: Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Before the light fades, who blows the whistle? : a narrative review on sports dementia

AimsTraumatic brain injury is a leading risk factor for degenerative conditions. Although in the past this was believed to affect mostly boxers, recent studies have expanded the at-risk population to include American football players, rugby players, hockey players and other athletes involved in contact sports. Hence, there has been growing interest in the media and the public at large on the short and long term impacts of head trauma in sportspersons. The aim of this study is provide an overview of the impact of traumatic brain injury in contact sports and the link to early onset dementia.MethodFor the purpose of this study we conducted a literature search using PubMed electronic base and Google scholar. The search was made in February 2021 and using the following keywords ‘early onset dementia’, ‘presenile dementia’, ‘traumatic brain injury’, ‘contact sports’, ‘sportsmen’, and ‘athletes’. The search words were used individually and in combination to gather relevant articles. Types of studies included were case reports, case series, cohorts, cross-sectional, editorial and newspaper articles.ResultMost of the published studies have shown significant associations between repeated head trauma and brain morphological changes evidenced by the presence of myelinated axons, astrocytosis, perivascular neuroinflammation and formation of phosphorylated Tau proteinopathy. These contribute significantly to alterations in axonal functioning and synaptic transmissions which sets the stage for neuronal degeneration. These changes affect both the macroscopic and microscopic structures with consequent neurochemical disturbances and functional deficits which, manifest primarily as executive dysfunction.ConclusionCurrent evidence supports an association between participation in contact sports and neurodegenerative disease, despite the protective aspects of sporting activities. Overall the studies reviewed have shown that brain injury remains a potent risk factor for the early onset dementia seen in sportspersons. Consequently, it is prudent for more proactive and precautionary measures to be put in place to reduce impacts of head injury and to better identify and manage brain injury in sports.

Distinguishing Dynamic Ca2+ Signals Originating from Different Entry Pathways in Microvascular Endothelial Cells

Background Pseudomonas aeruginosa ExoU infection causes formation of an infectious prion like tau proteinopathy in lung microvasculature, leading to respiratory endothelial cell injury. ExoU, a soluble phospholipase A2, disrupts the host cell membrane phospholipid chains, producing arachidonic acid (AA), and lysophosphatidic acid. A synthetic AA molecule has been shown to potently inhibit –cellular calcium channel transients through AA metabolites. Calcium transients have been linked to autophagy whereby the host endothelial cell entraps misfolded proteins. Although the mechanisms inherent to the cytotoxicity of ExoU infection are not clear, recent findings support an important role for AA metabolites. It is suspected that specific Ca2+ dynamics drive autophagy and inhibition of these transients by AA metabolites contributes to the pathologic signaling of Pseudomonas aeruginosa ExoU infection. The current project aims to evaluate whether our automated detection and analysis algorithm can effectively discern dynamic Ca2+ signals originating from distinct dynamic membrane ion channels. Method Microvascular endothelial cells (MVC's) were seeded and grown in 35mm glass-bottomed dishes. Cells were loaded with the fluorescent calcium indicator Cal-520 and assessed via confocal microscopy for calcium signals. Signals were recorded before and after treatment with either the 4α-PDD, which solicits Ca2+ entry through membrane TRPV4 channels, or the SERCA inhibitor thapsigargin (TG), which solicits Ca2+ entry through membrane store-operated Ca2+ channels. All image sequences were analyzed for frequency, duration, and amplitude of events using ImageJ and customized calcium signal detection software LC Pro. Data were expressed as mean ± SEM. Group data were subjected to Mann-Whitney U statistical method. Results We observed that TG treatments elicited Ca2+ signals with significant increase in mean amplitude of 7 ± 0.17 (F/F0) from mean amplitude of 4α-PDD treatment which was 5 ± 0.43 (F/F0) (p<0.05, n=3). The mean frequency of TG treatment was 1.46 ± 0.12 events/second, whereas mean frequency of 4α-PDD treatment was found to be 0.1 ± 0.04 events/second (p<0.05, n=3). Also, the mean event duration was 150 ± 17.56 seconds when subjected to TG as opposed to 4α-PDD treatment which elicited a mean event duration of 30 ± 7.12 seconds (p<0.05, n=3). Conclusion In these experiments, we were able to discern specific Ca2+ signaling profiles resulting from stimulation of two distinct Ca2+ entry pathways. Thus, application of automated dynamic signal tracking may provide a useful approach for distinguishing distinct Ca2+ entry mechanisms in future studies.

Dream Enactment Behavior Disorder Associated with Pallido-Nigro-Luysian Degeneration and Tau Proteinopathy.

Pallido-nigro-luysian atrophy (PNLA) is a rare neurodegenerative disorder with only a few cases reported to date. Although the clinical picture usually resembles progressive supranuclear palsy, pathological examination reveals more selective atrophy and loss of neurons in the globus pallidus, substantia nigra and subthalamic nucleus. To describe the clinical features and pathological findings of a patient with PNLA. Case report with clinico-pathological discussion. An 83-year-old man presented to our clinic with a vertical supranuclear gaze palsy, parkinsonism, gait impairment and sleep abnormalities suggestive of REM-sleep behavior disorder. Neuropathological examination 5 years after symptom onset revealed subcortical tau proteinopathy compatible with a PNLA pattern. There was also an associated mild degree of limbic/subcortical inflammatory response, Alzheimer's disease-related changes, as well as argyrophilic grain disease. We present a comprehensive clinico-pathological discussion of a patient with PNLA. Besides parkinsonism and vertical supranuclear gaze palsy, the patient also had a sleep disorder, clinically suggestive of REM behavioral disorder, which has not been previously reported in PNLA. We expand the clinical phenotype of this rare condition and provide neuropathological evidence for the associated abnormalities.

Recent Advances in Imaging of Preclinical, Sporadic, and Autosomal Dominant Alzheimer's Disease.

Observing Alzheimer's disease (AD) pathological changes in vivo with neuroimaging provides invaluable opportunities to understand and predict the course of disease. Neuroimaging AD biomarkers also allow for real-time tracking of disease-modifying treatment in clinical trials. With recent neuroimaging advances, along with the burgeoning availability of longitudinal neuroimaging data and big-data harmonization approaches, a more comprehensive evaluation of the disease has shed light on the topographical staging and temporal sequencing of the disease. Multimodal imaging approaches have also promoted the development of data-driven models of AD-associated pathological propagation of tau proteinopathies. Studies of autosomal dominant, early sporadic, and late sporadic courses of the disease have shed unique insights into the AD pathological cascade, particularly with regard to genetic vulnerabilities and the identification of potential drug targets. Further, neuroimaging markers of b-amyloid, tau, and neurodegeneration have provided a powerful tool for validation of novel fluid cerebrospinal and plasma markers. This review highlights some of the latest advances in the field of human neuroimaging in AD across these topics, particularly with respect to positron emission tomography and structural and functional magnetic resonance imaging.

Cryo-EM structures of tau filaments from Alzheimer\u2019s disease with PET ligand APN-1607

Tau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance.

This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large-scale emerging evidence. Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti-ferroptotic/iron compound in AD patients. Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well-established consequence of aging and inflammation, which are major theories of disease pathogenesis.