Interaction Of Tau Research Articles

Behavioral Evidence for a Tau and HIV-gp120 Interaction.

Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 years or older. Therefore, a new challenge looms as individuals living with HIV increase in age. There is concern that Alzheimer’s disease (AD) may become prevalent with an earlier onset of cognitive decline in people living with HIV (PLWH). Clinical data studies reported the presence of AD biomarkers in PLWH. However, the functional significance of the interaction between HIV or HIV viral proteins and AD biomarkers is still not well studied. The main goal of the present study is to address this knowledge gap by determining if the HIV envelope glycoprotein 120 (HIV-gp120) can affect the cognitive functions in the Tau mouse AD model. Male Tau and age-matched, wild-type (WT) control mice were treated intracerebroventricularly (ICV) with HIV-gp120. The animals were evaluated for cognitive function using a Y-maze. We found that HIV-gp120 altered cognitive function in Tau mice. Notably, HIV-gp120 was able to promote a cognitive decline in transgenic Tau (P301L) mice compared to the control (HIV-gp120 and WT). We provide the first in vivo evidence of a cognitive interaction between an HIV viral protein and Tau mice.

SH3- and actin-binding domains connect ADNP and SHANK3, revealing a fundamental shared mechanism underlying autism.

De novo heterozygous mutations in activity-dependent neuroprotective protein (ADNP) cause autistic ADNP syndrome. ADNP mutations impair microtubule (MT) function, essential for synaptic activity. The ADNP MT-associating fragment NAPVSIPQ (called NAP) contains an MT end-binding protein interacting domain, SxIP (mimicking the active-peptide, SKIP). We hypothesized that not all ADNP mutations are similarly deleterious and that the NAPV portion of NAPVSIPQ is biologically active. Using the eukaryotic linear motif (ELM) resource, we identified a Src homology 3 (SH3) domain-ligand association site in NAP responsible for controlling signaling pathways regulating the cytoskeleton, namely NAPVSIP. Altogether, we mapped multiple SH3-binding sites in ADNP. Comparisons of the effects of ADNP mutations p.Glu830synfs*83, p.Lys408Valfs*31, p.Ser404* on MT dynamics and Tau interactions (live-cell fluorescence-microscopy) suggested spared toxic function in p.Lys408Valfs*31, with a regained SH3-binding motif due to the frameshift insertion. Site-directed-mutagenesis, abolishing the p.Lys408Valfs*31 SH3-binding motif, produced MT toxicity. NAP normalized MT activities in the face of all ADNP mutations, although, SKIP, missing the SH3-binding motif, showed reduced efficacy in terms of MT-Tau interactions, as compared with NAP. Lastly, SH3 and multiple ankyrin repeat domains protein 3 (SHANK3), a major autism gene product, interact with the cytoskeleton through an actin-binding motif to modify behavior. Similarly, ELM analysis identified an actin-binding site on ADNP, suggesting direct SH3 and indirect SHANK3/ADNP associations. Actin co-immunoprecipitations from mouse brain extracts showed NAP-mediated normalization of Shank3-Adnp-actin interactions. Furthermore, NAP treatment ameliorated aberrant behavior in mice homozygous for the Shank3 ASD-linked InsG3680 mutation, revealing a fundamental shared mechanism between ADNP and SHANK3.

Mical modulates Tau toxicity via cysteine oxidation in vivo

Tau accumulation is clearly linked to pathogenesis in Alzheimer’s disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains. Mical is characterized by the presence of a flavoprotein monooxygenase domain that generates redox potential with which it can oxidize target proteins. In the well-established Drosophila Tauopathy model, we use genetic interactions to show that Mical alters Tau interactions with microtubules and the Actin cytoskeleton and greatly affects Tau aggregation propensity and Tau-associated toxicity and dysfunction. Exploration of the mechanism was pursued using a Mical inhibitor, a mutation in Mical that selectively disrupts its monooxygenase domain, Tau transgenes mutated at cysteine residues targeted by Mical and mass spectrometry analysis to quantify cysteine oxidation. The collective evidence strongly indicates that Mical’s redox activity mediates the effects on Tau via oxidation of Cys322. Importantly, we also validate results from the fly model in human Tauopathy samples by showing that MICAL1 is up-regulated in patient brains and co-localizes with Tau in Pick bodies. Our work provides mechanistic insights into the role of the Tau cysteine residues as redox-switches regulating the process of Tau self-assembly into inclusions in vivo, its function as a cytoskeletal protein and its effect on neuronal toxicity and dysfunction.

Interaction kinetics reveal distinct properties of conformational ensembles of three-repeat and four-repeat tau proteins.

Tau protein is an intrinsically disordered protein. Its physiological state is best described as a conformational ensemble (CE) of metastable structures interconverting on the local and molecular scale. The monoclonal antibody DC39C recognizes a linear C-terminal tau epitope, and as the tau interaction partner, its binding parameters report about tau CE. Association kinetics of DC39C binding, together with crosslinking mass spectrometry, show differences in the accessibility of the C terminus in CEs of tau isoforms. Furthermore, removal of the C terminus accelerated the aggregation kinetics of three-repeat tau proteins. Our results suggest a novel mechanism of splicing-driven regulation of the tau C-terminal domain with consequences on the specific roles of tau isoforms in microtubule assembly and pathological aggregation.

The Role of Post-Translational Modifications on the Structure and Function of Tau Protein

Involving addition of chemical groups or protein units to specific residues of the target protein, post-translational modifications (PTMs) alter the charge, hydrophobicity, and conformation of a protein, which in tune influences protein function, protein - protein interaction, and protein aggregation. While the occurrence of PTMs is dynamic and subject to regulations, conformational disorder of the target protein facilitates PTMs. The microtubule-associated protein tau is a typical intrinsically disordered protein that undergoes a variety of PTMs including phosphorylation, acetylation, ubiquitination, methylation, and oxidation. Accumulated evidence shows that these PTMs play a critical role in regulating tau-microtubule interaction, tau localization, tau degradation and aggregation, and reinforces the correlation between tau PTMs and pathogenesis of neurodegenerative disease. Here, we review tau PTMs with an emphasis on their influence on tau structure. With available biophysical characterization results, we describe how PTMs induce conformational changes in tau monomer and regulate tau aggregation. Compared to functional analysis of tau PTMs, biophysical characterization of tau PTMs is lagging. While it is challenging, characterizing the specific effects of PTMs on tau conformation and interaction is indispensable to unravel the tau PTM code.

A novel D-amino acid peptide with therapeutic potential (ISAD1) inhibits aggregation of neurotoxic disease-relevant mutant Tau and prevents Tau toxicity in vitro

BackgroundAlzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfunction, and neuronal death.MethodsWe aimed to develop novel therapeutic D-amino acid peptides as Tau fibrillization inhibitors. It has been previously demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-peptides, and these characteristics may render them suitable for in vivo applications. Using a phage display procedure against wild type full-length Tau (TauFL), we selected a novel Tau binding L-peptide and synthesized its D-amino acid version ISAD1 and its retro inversed form, ISAD1rev, respectively.ResultsWhile ISAD1rev inhibited Tau aggregation only moderately, ISAD1 bound to Tau in the aggregation-prone PHF6 region and inhibited fibrillization of TauFL, disease-associated mutant full-length Tau (TauFLΔK, TauFL-A152T, TauFL-P301L), and pro-aggregant repeat domain Tau mutant (TauRDΔK). ISAD1 and ISAD1rev induced the formation of large high molecular weight TauFL and TauRDΔK oligomers that lack proper Thioflavin-positive β-sheet conformation even at lower concentrations. In silico modeling of ISAD1 Tau interaction at the PHF6 site revealed a binding mode similar to those known for other PHF6 binding peptides. Cell culture experiments demonstrated that ISAD1 and its inverse form are taken up by N2a-TauRDΔK cells efficiently and prevent cytotoxicity of externally added Tau fibrils as well as of internally expressed TauRDΔK.ConclusionsISAD1 and related peptides may be suitable for therapy development of AD by promoting off-pathway assembly of Tau, thus preventing its toxicity.

Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

SUMMARYTau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau’s interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau’s role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.

1H MR spectroscopy biomarkers of neuronal and synaptic function are associated with tau deposition in cognitively unimpaired older adults

Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.

Synaptic tau and synaptogyrin‐3 are promising targets to tackle tauopathies

Different pathogenic conditions (Alzheimer's disease and other tauopathies) induce detachment of Tau protein from microtubules. Detached Tau accumulates at synapses and binds to synaptic vesicle-associated protein Synaptogyrin-3, hampering vesicle mobility and neurotransmitter release (Zhou et al., Nature Communications 2017). Lowering the levels of Synaptogyrin-3 alleviates synaptic dysfunction in fruit flies and mouse primary neurons McInnes et al., Neuron 2018).We pursued two strategies to lower Synaptogyrin-3 expression in a tauopathy mouse model (human P301S Tau-expressing mice; "PS19 mouse line"). We generated a synaptogyrin-3 knockout mouse usign CRISPR/Cas9 and crossed it with Tau P301S mice. In paralel, we designed several antisense oligonucleotides (ASOs) against common sequences of mouse and human Synaptogyrin-3.We showed that lowering expression of Synaptogyrin-3 is benign in mice, but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. We screened several anti-Synaptogyrin-3 ASOs in vitro and selected the most effective one to further study its effects in vivo.Lowering Synaptogyrin-3 is safe and sufficient to prevent cognitive decline in Tau P301S mice. Further research will determine the therapeutic potential of interfering with the interaction of Tau and Synaptogyrin-3 in the context of tauopathies.

The pathogenic mutation in tau defines the route of tau accumulation at presynapses.

Tau's primary localization is in the axons of neurons. At axons, Tau binds microtubuli and stabilizes them. Many of the pathogenic mutations interfere with binding of Tau to the microtubuli resulting in the relocation of Tau to different neuronal compartments, including the presynapse. Our lab has shown that Tau interact with synaptic vesicles via the synaptic vesicle protein, Synaptogyrin-3 and excessive Tau levels at presynapses results in the sequestration of synaptic vesicles compromising neurotransmission in Tau mutant fly and primary mouse neurons (Zhou, Nat. Commun. 2017; McInnes, Neuron, 2018). In addition, lowering Synaptogyrin-3 expression in TauP301L mutant mice reduces Tau-synaptic vesicle interactions and rescues Tau-mediated memory defects and synapse loss in these mice (Largo-Barrientos,Neuron, 2021). Although, the interaction of Tau with synaptic vesicles is reduced with lowering Synaptogyrin-3 expression, Tau continues to accumulate at presynapses. To reduce Tau levels and keep the presynapse healthy over time, we increased endosomal microautophagy by the expression of Hsc70-4 (Uytterhoeven, Neuron, 2015) in Tau mutant fly neurons . Despite, the overall reduced activity of degradation pathways in pathogenic conditions, we were able to reduce presynaptic TauP301L levels and restore reduced synaptic vesicle mobility and neurotransmission by increasing endosomal microautophagy. However, increasing endosomal microautophagy is not effective in lowering pathogenic TauV337M . Using a fluorescent timer attached to Tau, we show that older Tau is present in TauV337M compared to TauP301L mutant presynapses indicating that the turnover of TauV337M is hindered. On the contrary, with a fluorescence recovery after photobleaching assay we show that TauP301L is more mobile in axons compared to TauV337M indicating that TauP301L detaches more easily from the microtubuli. Together, these data show that both the detachment of Tau from microtubuli and defective turnover of Tau at presynapses contribute to the accumulation of Tau at presynapses and depending on the pathogenic mutation one of the two pathways plays a more prominent role in the accumulation of Tau at presynapses. Hence, these observations have further implications in the development of new therapies acting on Tau.

Investigating changes in the proteostasis capabilities of iPSC‐neurons during development and in FTD using iPSC‐neurons with MAPT mutations

AbstractBackgroundMutations in microtubule‐associated protein tau (MAPT) gene are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, e.g high levels of tau phosphorylation, are also present in early development. iPSC‐neurons have gene expression signatures similar to fetal neurons, and iPSC‐neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC‐neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis, we investigated the levels of proteasome subunits in developing iPSC derived neurons and measured the proteasome activity of iPSC‐neurons throughout development. To test whether manipulation of proteostasis in iPSC‐neurons could lead to tau pathology we treated cells with a proteasome inhibitor, and measured changes in total and phosphorylated tau, proteasome subunits and autophagy regulators.MethodsHuman cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at during neuronal development (DIV 0, 10, 30 and 100) and after proteasome inhibition treatments.ResultsWe show that proteasome activity decreases during the differentiation of iPSCs to cortical neurons, accompanied by a reduction in levels of the proteasome regulatory subunits Rpt6 and Rpn6. Proteasome inhibition in WT neurons does not lead to a significant change in total or phosphorylated tau levels but resulted in an increase in the autophagy associated protein BAG3, together with an induction of tau cleaved by caspase‐3 at Asp421.ConclusionProteasome activity decreases during the differentiation of iPSCs into neurons, which may be due to a reduction in in proteasome regulators. Our results suggest that proteasome inhibition causes an increase in tau cleavage which may be preferentially cleared through the autophagy pathway. The ability of these ‘fetal‐like’ neurons to adapt and upregulate their protein clearance system may be enhanced compared to FTD brain tissue. In ongoing work we are investigating proteasome expression and activity in FTD post‐mortem tissue as well as the localisation and interactions of tau and the proteasome after proteasome inhibition treatments.

Meta‐analysis of the associations of biomarkers of amyloid and tau with cognition in cognitively normal older adults

AbstractBackgroundConflicting evidence exists on the in vivo relationship of amyloid and tau levels to cognition among cognitively normal older adults. We conducted a meta‐analysis of reported relationships of biomarkers of amyloid or tau levels with baseline and change in cognition in cognitively normal older adults.MethodWe performed a literature search that returned studies between 2005 and January 2021 for studies reporting a relationship between amyloid or tau biomarkers measured via PET ligands, CSF, or plasma assays, with episodic memory or global cognition. Effect sizes were obtained for each study and weighted by sample size. For studies examining the same cohort, we selected effect sizes from the largest sample size available for each relationship of interest.ResultOne hundred and seven studies (89% reporting cross sectional measures and 62% reporting longitudinal) representing 26968 adults (82% characterized with amyloid measures and 23% with tau) were included. Amyloid levels showed a significant correlation with baseline and longitudinal global cognition (r=0.05, p<0001; r=0.05, p=0.021, respectively), and with baseline episodic memory (r=0.05, p=0.001). Tau was significantly correlated with baseline and longitudinal global cognition (r=0.08, p=0.004; r=0.08, p=0.01, respectively), and with longitudinal episodic memory (r=0.02, p=0.04), whereas the interaction of amyloid and tau was significantly correlated only with baseline global cognition (r=0.09, p=0.024). The overall estimated correlation between amyloid and tau was r=0.17.ConclusionIn older adults with normal cognition, there is a very small but significant relationship between baseline global cognition and amyloid, tau, and their interactive effect. Episodic memory had a very small but significant relationship with amyloid at baseline and with tau longitudinally. These findings could help determine power estimations for future clinical trials evaluating cognition in asymptomatic older adults. Effect size and power estimations from this meta‐analysis may be limited by unmeasured variability among studies in the timing of biomarker measurement, differences in cognitive assessments, or other cohort‐specific differences.

Post-translational modifications within tau paired helical filament nucleating motifs perturb microtubule interactions and oligomer formation

Post-translationally modified tau is the primary component of tau neurofibrillary tangles, a pathological hallmark of Alzheimer's disease and other tauopathies. Post-translational modifications (PTMs) within the tau microtubule (MT)-binding domain (MBD), which encompasses two hexapeptide motifs that act as critical nucleating regions for tau aggregation, can potentially modulate tau aggregation as well as interactions with MTs and membranes. Here, we characterize the effects of a recently discovered tau PTM, lysine succinylation, on tau–tubulin interactions and compare these to the effects of two previously reported MBD modifications, lysine acetylation and tyrosine phosphorylation. As generation of site-specific PTMs in proteins is challenging, we used short synthetic peptides to quantify the effects on tubulin binding of three site-specific PTMs located within the PHF6∗ (paired helical filament [PHF] residues 275–280) and PHF6 (residues 306–311) hexapeptide motifs: K280 acetylation, Y310 phosphorylation, and K311 succinylation. We compared these effects to those observed for MBD PTM-mimetic point mutations K280Q, Y310E, and K311E. Finally, we evaluated the effects of these PTM-mimetic mutations on MBD membrane binding and membrane-induced fibril and oligomer formation. We found that all three PTMs perturb tau MT binding, with Y310 phosphorylation exerting the strongest effect. PTM-mimetic mutations partially recapitulated the effects of the PTMs on MT binding and also disrupted tau membrane binding and membrane-induced oligomer and fibril formation. These results imply that these PTMs, including the novel and Alzheimer's disease–specific succinylation of tau K311, may influence both the physiological and pathological interactions of tau and thus represent targets for therapeutic intervention.

Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism.

Pathologic tau modifications are characteristic of Alzheimer's disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α, β, and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1α and PP1γ isoforms, but not PP1β, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons.SIGNIFICANCE STATEMENT Tau pathology is closely associated with neurodegeneration in Alzheimer's disease and other tauopathies, but the toxic mechanisms remain a debated topic. We previously proposed that pathologic tau forms induce dysfunction and degeneration through aberrant activation of a PP1-dependent pathway that disrupts axonal transport. Here, we show that tau directly interacts with specific PP1 isoforms, increasing levels of active PP1. Pathogenic tau mutations enhance this interaction, further increasing active PP1 levels and impairing axonal transport in isolated squid axoplasm and primary hippocampal neurons. Mutant-tau-mediated impairment of axonal transport was mediated by PP1γ and a phosphatase-activating domain located at the amino terminus of tau. This work has important implications for understanding and potentially mitigating tau-mediated neurotoxicity in tauopathies.

Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.

FYN, SARS-CoV-2, and IFITM3 in the neurobiology of Alzheimer's disease

Introduction(IFITM3) is an innate immune protein that has been identified as a novel γ-secretase (γs) modulator. FYN is a kinase that stabilizes IFITM3 on the membrane, primes APP for amyloidogenic γs processing and mediates tau oligomerization. The purpose of this study is to explore the role of FYN and IFITM3 in AD and COVID-19, expanding on previous research from our group. MethodsA 520 gene signature containing FYN and IFITM3 (termed Ia) was extracted from a previously published meta-analysis of Alzheimer's disease (AD) bulk- and single nuclei sequencing data. Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression per CNS site and cellular type. Confirmatory analyses, gene set enrichment analysis (GSEA) on Ia was performed to detect overlapping enriched biological networks between COVID-19 with AD. ResultsBulk RNA data analysis revealed that IFITM3 and FYN were overexpressed in two CNS regions in AD vs. Controls: the temporal cortex Wilcoxon p-value=1.3e-6) and the parahippocampal cortex Wilcoxon p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neurons, glial and endothelial cells donated b AD patients, when compared to controls. DiscussionIFITM3 and FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. Within the context of SARS-CoV-2 induced tau aggregation and interactions between tau and Ab1–42, the FYN – IFITM3 regulome may outline an important innate immunity element responsive to viral infection and IFN-I signaling in both AD and COVID-19.

Membrane interaction and disulphide-bridge formation in the unconventional secretion of Tau.

Misfolded, pathological tau protein propagates from cell to cell causing neuronal degeneration in Alzheimer’s disease and other tauopathies. The molecular mechanisms of this process have remained elusive. Unconventional secretion of tau takes place via several different routes, including direct penetration through the plasma membrane. Here, we show that tau secretion requires membrane interaction via disulphide bridge formation. Mutating residues that reduce tau interaction with membranes or formation of disulphide bridges decrease both tau secretion from cells, and penetration through artificial lipid membranes. Our results demonstrate that tau is indeed able to penetrate protein-free membranes in a process independent of active cellular processes and that both membrane interaction and disulphide bridge formation are needed for this process. QUARK-based de novo modelling of the second and third microtubule-binding repeat domains (MTBDs), in which the two cysteine residues of 4R isoforms of tau are located, supports the concept that this region of tau could form transient amphipathic helices for membrane interaction.

Regulation of Synapse Weakening through Interactions of the Microtubule Associated Protein Tau with PACSIN1.

Hyperphosphorylation of the microtubule associated protein tau (tau) is inextricably linked to several neurodegenerative diseases, collectively termed tauopathies, in which synapse dysfunction occurs through largely unidentified mechanisms. Our research aimed to uncover molecular mechanisms by which phosphorylation of tau (pTau) affects synapse function. Using combined molecular and electrophysiological analysis with in vitro genetic knock-in of phosphorylation mutant human tau in male rat CA1 hippocampal neurons, we show an interplay between tau and protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1) that regulates synapse function. pTau at serine residues 396/404 decreases tau:PACSIN1 binding and evokes PACSIN1-dependent functional and structural synapse weakening. Knock-down of tau or PACSIN1 increases AMPA receptor (AMPAR)-mediated current at extrasynaptic regions, supporting a role for these proteins in affecting AMPAR trafficking. The pTau-induced PACSIN1 dissociation may represent a pathophysiological regulator of synapse function that underlies tauopathy-associated synapse defects.SIGNIFICANCE STATEMENT Knowledge is still lacking for how hyperphosphorylation of tau and its effectors lead to synaptic and neuronal dysfunction. Our results provide crucial insight for this mechanistic understanding; we show that specific tau phosphorylation events modulate its protein interaction with PACSIN1 and thus elicits synapse weakening likely through PACSIN1-dependent regulation of AMPA receptor (AMPAR) trafficking. These findings develop our understanding of molecular events that may be relevant to cellular changes underpinning tauopathy-associated neurodegenerative diseases.

Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults.

Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment. Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aβ)42 /Aβ40 and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4. We observed a significant CSF Aβ42 /Aβ40 × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes. NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.

Role of the Lipid Membrane and Membrane Proteins in Tau Pathology.

Abnormal accumulation of misfolded tau aggregates is a pathological hallmark of various tauopathies including Alzheimer’s disease (AD). Although tau is a cytosolic microtubule-associated protein enriched in neurons, it is also found in extracellular milieu, such as interstitial fluid, cerebrospinal fluid, and blood. Accumulating evidence showed that pathological tau spreads along anatomically connected areas in the brain through intercellular transmission and templated misfolding, thereby inducing neurodegeneration and cognitive dysfunction. In line with this, the spatiotemporal spreading of tau pathology is closely correlated with cognitive decline in AD patients. Although the secretion and uptake of tau involve multiple different pathways depending on tau species and cell types, a growing body of evidence suggested that tau is largely secreted in a vesicle-free forms. In this regard, the interaction of vesicle-free tau with membrane is gaining growing attention due to its importance for both of tau secretion and uptake as well as aggregation. Here, we review the recent literature on the mechanisms of the tau-membrane interaction and highlights the roles of lipids and proteins at the membrane in the tau-membrane interaction as well as tau aggregation.