Interaction Of Tau Research Articles

Integrative Network Analysis Reveals Novel Moderators of Aβ-Tau Interaction in Alzheimer's Disease.

Although interactions between amyloid-beta and tau proteins have been implicated in Alzheimer's disease (AD), the precise mechanisms by which these interactions contribute to disease progression are not yet fully understood. Moreover, despite the growing application of deep learning in various biomedical fields, its application in integrating networks to analyze disease mechanisms in AD research remains limited. In this study, we employed BIONIC, a deep learning-based network integration method, to integrate proteomics and protein-protein interaction data, with an aim to uncover factors that moderate the effects of the Aβ-tau interaction on mild cognitive impairment (MCI) and early-stage AD. Proteomic data from the ROSMAP cohort were integrated with protein-protein interaction (PPI) data using a Deep Learning-based model. Linear regression analysis was applied to histopathological and gene expression data, and mutual information was used to detect moderating factors. Statistical significance was determined using the Benjamini-Hochberg correction (p < 0.05). Our results suggested that astrocytes and GPNMB+ microglia moderate the Aβ-tau interaction. Based on linear regression with histopathological and gene expression data, GFAP and IBA1 levels and GPNMB gene expression positively contributed to the interaction of tau with Aβ in non-dementia cases, replicating the results of the network analysis. These findings indicate that GPNMB+ microglia moderate the Aβ-tau interaction in early AD and therefore are a novel therapeutic target. To facilitate further research, we have made the integrated network available as a visualization tool for the scientific community (URL: https://igcore.cloud/GerOmics/AlzPPMap).

Illana Gozes: From the pivotal discovery of activity-dependent neuroprotective protein (ADNP) through its investigational drug davunetide: brain molecular medicine providing hope for autism, schizophrenia, and Alzheimer's disease

Professor Illana Gozes, Ph.D., is a faculty member at Tel Aviv University. Formerly holding the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, she now directs the Dr. Diana and Zelma Elton Laboratory for Molecular Neuroendocrinology. A world-renowned neurochemist, Professor Gozes currently serves as the President of the European Society for Neurochemistry and Vice President of Drug Development at ExoNavis Therapeutics Ltd. Her groundbreaking research began in the late 1970s and early 1980s when she discovered multiple tubulin forms within a single neuron. She demonstrated that these forms evolve with brain development, play a crucial role in synapse formation, and can be identified using monoclonal tubulin antibodies. At the forefront of molecular neuroscience in the 1980s, Professor Gozes became the first to clone the gene encoding vasoactive intestinal peptide (VIP), a key regulatory neuropeptide in the brain. Her research revealed increased VIP expression during synapse formation. In her quest to identify proteins activated by VIP and facilitate neuro-glial interaction, the Gozes laboratory discovered and cloned a novel protein: activity-dependent neuroprotective protein (ADNP). Subsequent research established ADNP's essential role in brain formation and function. Through a series of highly cited articles, Professor Gozes demonstrated that ADNP regulates thousands of essential genes during brain development in a sex-dependent manner and associates with an intricate array of vital proteins. She uncovered ADNP's key role in autophagy and schizophrenia, revealed a fundamental shared mechanism in autism involving critical binding of ADNP with SHANK3 and actin, and showed ADNP's regulation of microtubule dynamics and Tau interaction, which protects against tauopathy. Furthermore, she discovered somatic mutations in ADNP and related genes in Alzheimer's disease, paralleling tauopathy. Her pioneering work on ADNP-deficient mouse models predicted the ADNP syndrome, an autistic/intellectual disability syndrome driven by de novo mutations in ADNP and presenting with tauopathy. Professor Gozes took a reductionist approach to discover an active site in ADNP, leading to the development of the investigational drug davunetide (NAP). This compound has shown promise in protecting against ADNP deficiency/mutations in animal models and in clinical trials. It has been tested in women suffering from progressive supranuclear palsy (PSP), a pure tauopathy, and in individuals with prodromal Alzheimer's disease, demonstrating effects in a sex-dependent manner. Further promise was shown in schizophrenia patients, suggesting improvement in real-world problem solving and task performance. We are honored that Professor Gozes has agreed to share her life's journey with our readers in this Genomic Press Interview.

Multivalency drives interactions of alpha-synuclein fibrils with tau.

Age-related neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by deposits of protein aggregates, or amyloid, in various regions of the brain. Historically, aggregation of a single protein was observed to be correlated with these different pathologies: tau in AD and α-synuclein (αS) in PD. However, there is increasing evidence that the pathologies of these two diseases overlap, and the individual proteins may even promote each other's aggregation. Both tau and αS are intrinsically disordered proteins (IDPs), lacking stable secondary and tertiary structure under physiological conditions. In this study we used a combination of biochemical and biophysical techniques to interrogate the interaction of tau with both soluble and fibrillar αS. Fluorescence correlation spectroscopy (FCS) was used to assess the interactions of specific domains of fluorescently labeled tau with full length and C-terminally truncated αS in both monomer and fibrillar forms. We found that full-length tau as well as individual tau domains interact with monomer αS weakly, but this interaction is much more pronounced with αS aggregates. αS aggregates also mildly slow the rate of tau aggregation, although not the final degree of aggregation. Our findings suggest that co-occurrence of tau and αS in disease are more likely to occur through monomer-fiber binding interactions, rather than monomer-monomer or co-aggregation.

Behavioral neuroscience in zebrafish: unravelling the complexity of brain-behavior relationships.

This paper reviews the utility of zebrafish (Danio rerio) as a model system for exploring neurobehavioral phenomena in preclinical research, focusing on physiological processes, disorders, and neurotoxicity biomarkers. A comprehensive review of the current literature was conducted to summarize the various behavioral characteristics of zebrafish. The study examined the etiological agents used to induce neurotoxicity and the biomarkers involved, including Aβ42, tau, MMP-13, MAO, NF-Кβ, and GFAP. Additionally, the different zebrafish study models and their responses to neurobehavioral analysis were discussed. The review identified several key biomarkers of neurotoxicity in zebrafish, each impacting different aspects of neurogenesis, inflammation, and neurodegeneration. Aβ42 was found to alter neuronal growth and stem cell function. Tau's interaction with tubulin affected microtubule stability and led to tauopathies under pathological conditions. MMP-13 was linked to oxidative assault and sensory neuron degeneration. MAO plays a role in neurotransmitter metabolism and neurotoxicity conversion. NF-Кβ was involved in pro-inflammatory pathways, and GFAP was indicative of neuroinflammation and astroglial activation. Zebrafish provide a valuable model for neurobehavioral research, adhering to the "3Rs" philosophy. Their neurotoxicity biomarkers offer insights into the mechanisms of neurogenesis, inflammation, and neurodegeneration. This model system aids in evaluating physiological and pathological conditions, enhancing our understanding of neurobehavioral phenomena and potential therapeutic interventions.

Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults.

Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aβ positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aβ positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aβ pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.

Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid-β (Aβ) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to cell in a prion-like manner and induce native proteins to become pathological. The entorhinal cortex (EC) is among the earliest areas affected by tau accumulation along with volume reduction and neurodegeneration. Neuron-glia interactions have recently come into focus; however, the role of microglia and astroglia in the pathogenesis of AD remains unclear. Proteomic approaches allow the determination of changes in the proteome to better understand the pathology underlying AD. Bioinformatic analysis of proteomic data was performed to compare ECs from AD and non-AD human brain tissue. To validate the proteomic results, western blot, immunofluorescence, and confocal studies were carried out. The findings revealed that the most disturbed signaling pathway was synaptogenesis. Because of their involvement in synapse function, relationship with Aβ and tau proteins and interactions in the pathway analysis, three proteins were selected for in-depth study: HSP90AA1, PTK2B, and ANXA2. All these proteins showed colocalization with neurons and/or astroglia and microglia and with pathological Aβ and tau proteins. In particular, ANXA2, which is overexpressed in AD, colocalized with amoeboid microglial cells and Aβ plaques surrounded by astrocytes. Taken together, the evidence suggests that unbalanced expression of HSP90AA1, PTK2B, and ANXA2 may play a significant role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells in the human EC in AD.

Interaction of Tau with G-Protein-Coupled Purinergic P2Y12 Receptor by Molecular Docking and Molecular Dynamic Simulation.

Alzheimer's disease, a progressive neurological disorder, is characterized by the accumulation of neurofibrillary tangles and senile plaques by Tau and amyloid-β, respectively, in the brain microenvironment. The misfolded protein aggregates interact with several components of neuronal and glial cells such as membrane lipids, receptors, transporters, enzymes, cytoskeletal proteins, etc. Under pathological conditions, Tau interacts with several G-protein-coupled receptors (GPCRs), which undergoes either receptor signaling or desensitization followed by internalization of the protein complex. The purinergic GPCR, P2Y12 which is expressed in microglial cells, plays a key role in its activation and migration. Microglial cells sense and migrate to the site of injury aided by P2Y12 receptor that interacts with ADP released from damaged cells. P2Y12 receptor also interacts with misfolded Tau accumulated at the extracellular space and promotes receptor-mediated internalization. Immunocolocalization and co-immunoprecipitation studies demonstrated the interaction of Tau species with the P2Y12 receptor. Later, in-silico analyses were carried out with the repeat domain of Tau (TauRD), which has been identified as the interacting partner of P2Y12 receptor by in-vitro studies. Molecular docking and molecular dynamics simulation studies show the stability and the type of interaction in TauRD-receptor complex. Tau interaction with P2Y12 receptor plays a significant role in maintaining the active state of microglia which could lead to neuroinflammation and neuronal damage in AD brain. Hence, blocking P2Y12-Tau interaction and P2Y12-mediated Tau internalization in microglial cells could be possible therapeutic strategies in downregulating the severity of neuroinflammation in AD.

The role of microtubule-associated protein tau in netrin-1 attractive signaling.

Direct binding of netrin receptors with dynamic microtubules (MTs) in the neuronal growth cone plays an important role in netrin-mediated axon guidance. However, how netrin-1 (NTN1) regulates MT dynamics in axon turning remains a major unanswered question. Here, we show that the coupling of netrin-1 receptor DCC with tau (MAPT)-regulated MTs is involved in netrin-1-promoted axon attraction. Tau directly interacts with DCC and partially overlaps with DCC in the growth cone of primary neurons. Netrin-1 induces this interaction and the colocalization of DCC and tau in the growth cone. The netrin-1-induced interaction of tau with DCC relies on MT dynamics and TUBB3, a highly dynamic β-tubulin isotype in developing neurons. Netrin-1 increased cosedimentation of DCC with tau and TUBB3 in MTs, and knockdown of either tau or TUBB3 mutually blocked this effect. Downregulation of endogenous tau levels by tau shRNAs inhibited netrin-1-induced axon outgrowth, branching and commissural axon attraction in vitro, and led to defects in spinal commissural axon projection in vivo. These findings suggest that tau is a key MT-associated protein coupling DCC with MT dynamics in netrin-1-promoted axon attraction.

CHORDC1, the novel interacting partner of tau protein.

Alzheimer's disease is currently not curable. Almost all attempts to identify disease-modifying drugs failed and the causes of disease etiology are not well understood. Neurofibrillary tangles composed of pathological tau protein belong to the main hallmarks of this disease. Identification of novel physiological and pathological tau interacting proteins may lead to a better understanding of Alzheimer's disease pathology and tau physiology and therefore we performed a screening of the brain library by a yeast two-hybrid system intending to identify new tau interaction partners. We identified CHORDC1 (cysteine and histidine-rich domain-containing protein 1) as a novel tau interaction partner by this approach. The CHORDC1-tau interaction was validated by co-immunoprecipitation from rat brain tissues and by in vitro co-localization in the cellular model expressing full-length human tau protein. We believe that our results can be useful for researchers studying tau protein in health and disease.

A Novel Mouse Model of Alzheimer’s Disease Exhibits Pathology through Synergistic Interactions of Amyloid-β, Tau, and Reactive Astrogliosis

A Novel Mouse Model of Alzheimer’s Disease Exhibits Pathology through Synergistic Interactions of Amyloid-β, Tau, and Reactive Astrogliosis

Interaction of full-length Tau with negatively charged lipid membranes leads to polymorphic aggregates.

The Tau protein is implicated in various diseases collectively known as tauopathies, including Alzheimer's disease and frontotemporal dementia. The precise mechanism underlying Tau pathogenicity remains elusive. Recently, the role of lipids has garnered interest due to their implications in Tau aggregation, secretion, uptake, and pathogenic dysregulation. Previous investigations have highlighted critical aspects: (i) Tau's tendency to aggregate into fibers when interacting with negatively charged lipids, (ii) its ability to form structured species upon contact with anionic membranes, and (iii) the potential disruption of the membrane upon Tau binding. In this study, we examine the disease-associated P301L mutation of the 2N4R isoform of Tau and its effects on membranes composed on phosphatidylserine (PS) lipids. Aggregation studies and liposome leakage assays demonstrate Tau's ability to bind to anionic lipid vesicles, leading to membrane disruption. Attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) reveals the accumulation of Tau on the membrane surface without protein insertion, structuration, or lipid removal. Plasmon waveguide resonance (PWR) demonstrates a strong binding of Tau on PS bilayers with an apparent Kd in the micromolar range, indicating the deposition of a thick protein layer. Atomic force microscopy (AFM) real-time imaging allows the observation of partial lipid solubilization and the deposition of polymorphic aggregates in the form of thick patches and fibrillary structures resembling amyloid fibers, which could grow from a combination of extracted anionic phospholipids from the membrane and Tau protein. This study deepens our understanding of full-length Tau's multifaceted interactions with lipids, shedding light on potential mechanisms leading to the formation of pathogenic Tau assemblies.

Interaction of Tau with Kinesin-1: Effect of Kinesin-1 Heavy Chain Elimination on Autophagy-Mediated Mutant Tau Degradation.

Natively unfolded tau has a low propensity to form aggregates, but in tauopathies, such as Alzheimer's disease (AD), tau aggregates into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Multiple intracellular transport pathways utilize kinesin-1, a plus-end-directed microtubule-based motor. Kinesin-1 is crucial in various neurodegenerative diseases as it transports multiple cargoes along the microtubules (MT). Kinesin-1 proteins cannot progress along MTs due to an accumulation of tau on their surfaces. Although kinesin-1-mediated neuronal transport dysfunction is well-documented in other neurodegenerative diseases, its role in AD has received less attention. Very recently, we have shown that knocking down and knocking out of kinesin-1 heavy chain (KIF5B KO) expression significantly reduced the level and stability of tau in cells and tau transgenic mice, respectively. Here, we report that tau interacts with the motor domain of KIF5B in vivo and in vitro, possibly through its microtubule-binding repeat domain. This interaction leads to the inhibition of the ATPase activity of the motor domain. In addition, the KIF5B KO results in autophagy initiation, which subsequently assists in tau degradation. The mechanisms behind KIF5B KO-mediated tau degradation seem to involve its interaction with tau, promoting the trafficking of tau through retrograde transport into autophagosomes for subsequent lysosomal degradation of tau. Our results suggest how KIF5B removal facilitates the movement of autophagosomes toward lysosomes for efficient tau degradation. This mechanism can be enabled through the downregulation of kinesin-1 or the disruption of the association between kinesin-1 and tau, particularly in cases when neurons perceive disturbances in intercellular axonal transport.

Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-β toxicity and network hyperexcitability

Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-β–induced dysfunction in preclinical models of AD and also prevents amyloid-β–independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain–containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain–containing proteins ameliorates amyloid-β–induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-β–induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.

Insights into Novel Therapies and the Pathogenesis of Alzheimer's disease, and the Possible Role of COVID-19

The Wisniewski laboratory has helped develop novel biomarkers and therapeutic approaches to AD, particular immunotherapeutic approaches that affect both the adaptive and innate immune systems. We have developed a means to stimulate innate immunity to ameliorate AD pathology, which we have tested in aged squirrel monkeys, and now are conducting a phase I clinical trial. We have also developed both active and passive immunization that specifically targets the dominant β-sheet secondary structure of multiple toxic oligomers concurrently (including both Aβ and tau oligomers). Recently we have also documented the neurological manifestations of SARS-CoV-2 infection (in particular cognitive dysfunction) and associated biomarkers of neurodegeneration and neuroinflammation. We have also developed an unbiased proteomic methodology that produces robust data utilizing archival formalin, fixed paraffin embedded human tissue, using this method to perform the most extensive proteomic analysis of amyloid plaques and the phosphorylated tau interaction, as well as to characterize the amyloid proteome of distinct subtypes of AD including rapidly progressive AD and AD in Down syndrome. These studies have helped enhance the understanding of the pathogenesis of AD, and also with the development of novel therapies.

Inter‐network connectivity of early Aβ and tau‐seeded functional networks is associated with longitudinal tau accumulation in at‐risk cognitively normal older adults

AbstractBackgroundFunctional connectivity (FC) between networks may be related to Aβ and tau interactions in preclinical Alzheimer’s disease (AD). Here, we investigated associations between inter‐network FC of early Aβ and tau‐seeded networks, APOEe4, global Aβ, and longitudinal tau accumulation in cognitively healthy older adults (OA).MethodVoxel‐wise PiB‐PET and FTP‐PET OA images were ordered by increasing pathology burden and iteratively compared to a reference set of young adult (YA) PET images. Peak voxels of the earliest significant differences were matched to Brainnetome ROIs and used to construct separate Aβ and tau‐seeded networks within a group average YA FC matrix (Figure 1). Next, the average inter‐network FC between all node pairs between the networks was calculated in OA (n = 60; aged 77.6±5.5). Longitudinal FTP slopes of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) were estimated using linear mixed effects models. Linear regression was used to assess relationships between baseline inter‐network FC, APOEe4 status, baseline global PiB, and both a prior ROI and voxel‐wise FTP slopes.ResultIn all OA, inter‐network FC was not associated with baseline global PIB (t(58) = ‐0.23, p = 0.82), EC FTP slope (t(58) = 0.49, p = 0.63), or ITG FTP slope (t(58) = ‐1.45, p = 0.15). There was a significant interaction between baseline global PiB status and inter‐network FC where FC was negatively associated with ITG FTP slope in PiB+ participants (t(56) = ‐2.01, p = 0.04; Figure 2A). There was also a significant interaction between APOEe4 status and inter‐network FC in predicting ITG FTP slope with a negative relationship only in e4 carriers (t(56) = ‐3.19, p = 0.003; Figure 2B). Voxel‐wise analyses revealed significant negative relationships between inter‐network FC and FTP slope in the left fusiform gyrus and ITG in PiB+ participants and e4 carriers, respectively (Figure 2C‐D).ConclusionLower baseline inter‐network FC of early Aβ and tau‐seeded networks was associated with greater longitudinal tau accumulation outside of the medial temporal lobe (MTL) in cognitively normal OA with higher AD risk (i.e., elevated Aβ or APOEe4). Our results suggest that this network disruption is associated with faster rates of tau accumulation outside of the MTL, possibly reflecting a later stage in the preclinical progression to AD.

Relationship between loss of awareness of cognitive decline and tau pathology in the Alzheimer’s disease spectrum: modulatory role of resting‐state functional connectivity

AbstractBackgroundPatients with Alzheimer’s disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum.MethodWe included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education.ResultHolding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p&lt;0.01). Lower awareness was associated with a higher tau burden in all 7 networks (Table2). Interaction effects between tau and FC were observed. Specifically, reduced awareness was associated with high tau burden when the salience network was less functionally connected (Figure1A; β = ‐0.23, p = 0.02) and when the dorsal attention network was more functionally connected (Figure1B; β = 0.70, p = 0.03). For all other networks, the relationship between awareness and tau was not modified by the FC of the same network (Table2).ConclusionThese findings provide new insights into the neuropathological correlates of anosognosia in AD. It suggests that anosognosia is not only due to local pathology in single brain areas but also to altered connectivity between them, especially within self‐referential networks.

Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure

Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer’s disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.

Antagonistic Amyloid‐β and tau interactions with T1‐weighted/T2‐weighted magnetic resonance ratio in Alzheimer’s disesase continuum

AbstractBackgroundTau protein has been reported as a major cause of neurodegeneration in Alzheimer’s disease (AD) continuum. Decrease of T1‐weighted/T2‐weighted magnetic resonace (MR) ratio has been proposed as a measure of demyelination related to neurodegeneration, but some previous researches showed contradictory increase in several brain regions, which was considered as the effecs of other microstructures such as the amyloid‐related iron deposition. Therefore, amyloid β and tau proteins appear to affect the T1w/T2w ratio antagonistically, making their relationship need to be elucidated in order to unambiguously interpret the ratio.MethodWe obtained 221 individuals which include T1‐ and T2‐weighted MR images, and 18F‐florbetapir‐ and 18F‐flortaucipir‐PET images from ADNI. The subjects were then divided into four subgroups based on the status of global Aβ and tau accumulation amount: A‐T‐, A‐T+, A+T‐, and A+T+. We determined positive amyloid status(A+) as global Aβ PET SUVR &gt; 1.11. When determining tau positivity, we used entorhinal cortex (EC) as the earliest tau accumulation region to selectively include tau‐negative individuals while amyloid is being presented. Group differences in regional T1w/T2w ratio values were evaluated.ResultWe found significant group differences in various cortical regions, but also observed distinct effects of Aβ and tau for the T1w/T2w difference. First of all, Aβ and tau affect the T1w/T2w ratio in an opposite direction. A+ individuals have greater T1w/T2w ratio values across wide cortical regions compared to A‐ individuals for both T‐ and T+ groups. However, A‐T+ groups have smaller T1w/T2w ratio values than A‐T‐ groups, while the significant group difference was observed across relatively few cortical regions. Second, Aβ has stronger effect on the T1w/T2w ratio than tau. Specifically, the group difference between A+T+ and A+T‐ shows that Aβ increase the ratio values more strongly than tau reduces the ratio values due to greater accumulation of Aβ in the A+T+ than A+T‐.ConclusionIn this work, we observed the antagonistic interaction of Aβ and tau with T1w/T2w ratio, while more interestingly, we also found that Aβ causes high T1w/T2w ratio, more than tau causes demyelination, followed by lowering T1w/T2w ratio.

Structure challenges in the multivalency of Tau-microtubule interactions.

Structural studies aiming to visualize the interaction of Tau with microtubules (MTs) face several challenges, the main concerning the fact that Tau has multiple MT-interacting regions. In particular, the four (or three) pseudo-repeats of Tau bind to identical elements along the MT lattice but do it through non-identical residues. In addition, any given Tau molecule can use all its repeats or just one for its engagement with MTs. Finally, the binding of one Tau is not necessarily in register with respect to the next one. The mismatch in the MT and Tau repeats, therefore, challenges conventional modes of image analysis when visualizing these samples using cryo-electron microscopy. This commentary is dedicated to those challenges and ways to circumvent them while aiming for an atomic description of the Tau-tubulin interaction.

Stability and bifurcation analysis of Alzheimer's disease model with diffusion and three delays.

A reaction-diffusion Alzheimer's disease model with three delays, which describes the interaction of β-amyloid deposition, pathologic tau, and neurodegeneration biomarkers, is investigated. The existence of delays promotes the model to display rich dynamics. Specifically, the conditions for stability of equilibrium and periodic oscillation behaviors generated by Hopf bifurcations can be deduced when delay σ (σ=σ1+σ2) or σ3 is selected as a bifurcation parameter. In addition, when delay σ and σ3 are selected as bifurcation parameters, the stability switching curves and the stable region are obtained by using an algebraic method, and the conditions for the existence of Hopf bifurcations can also be derived. The effects of time delays, diffusion, and treatment on biomarkers are discussed via numerical simulations. Furthermore, sensitivity analysis at multiple time points is drawn, indicating that different targeted therapies should be taken at different stages of development, which has certain guiding significance for the treatment of Alzheimer's disease.