Reduces Tau Pathology Research Articles

A Multi-Criteria Decision Aid Tool for Radiopharmaceutical Selection in Tau PET Imaging.

The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer's disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)-tau pathological lesions, but this is possible only after death and only shows tau in the portion of brain sampled. Positron emission tomography (PET) imaging allows both the quantitative and qualitative analysis of pathology over the whole brain of a living subject. The ability to detect and quantify tau pathology in vivo using PET can aid in the early diagnosis of AD, provide a way to monitor disease progression, and determine the effectiveness of therapeutic interventions aimed at reducing tau pathology. Several tau-specific PET radiotracers are now available for research purposes, and one is approved for clinical use. This study aims to analyze, compare, and rank currently available tau PET radiotracers using the fuzzy preference ranking organization method for enrichment of evaluations (PROMETHEE), which is a multi-criteria decision-making (MCDM) tool. The evaluation is based on relatively weighted criteria, such as specificity, target binding affinity, brain uptake, brain penetration, and rates of adverse reactions. Based on the selected criteria and assigned weights, this study shows that a second-generation tau tracer, [18F]RO-948, may be the most favorable. This flexible method can be extended and updated to include new tracers, additional criteria, and modified weights to help researchers and clinicians select the optimal tau PET tracer for specific purposes. Additional work is needed to confirm these results, including a systematic approach to defining and weighting criteria and clinical validation of tracers in different diseases and patient populations.

A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy.

Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopathies, including Alzheimer's disease. Prolyl oligopeptidase is a serine protease that is associated with neurodegeneration, and its inhibition normalizes PP2A activity without toxicity under pathological conditions. Here, we assessed whether prolyl oligopeptidase inhibition could protect against tau-mediated toxicity in cellular models in vitro and in the PS19 transgenic mouse model of tauopathy carrying the human tau-P301S mutation. We show that inhibition of prolyl oligopeptidase with the inhibitor KYP-2047 reduced tau aggregation in tau-transfected HEK-293 cells and N2A cells as well as in human iPSC-derived neurons carrying either the P301L or tau-A152T mutation. Treatment with KYP-2047 resulted in increased PP2A activity and activation of autophagic flux in HEK-293 cells and N2A cells and in patient-derived iNeurons, as indicated by changes in autophagosome and autophagy receptor markers; this contributed to clearance of insoluble tau. Furthermore, treatment of PS19 transgenic mice for 1 month with KYP-2047 reduced tau burden in the brain and cerebrospinal fluid and slowed cognitive decline according to several behavioral tests. In addition, a reduction in an oxidative stress marker was seen in mouse brains after KYP-2047 treatment. This study suggests that inhibition of prolyl oligopeptidase could help to ameliorate tau-dependent neurodegeneration.

Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b

BackgroundA key histopathological hallmark of Alzheimer’s disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes.MethodsIn this work, we employed bioinformatics analysis—including pathway enrichment and causal reasoning—of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure.ResultsCombining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled “Superpathway of cholesterol biosynthesis” and “Granulocyte adhesion and diapedesis”. With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins.ConclusionsThis study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.

Discovery of DA‐7503 as a Novel Tau‐targeted Therapeutic Candidate for the Treatment of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is a late‐onset, progressive, age‐dependent neurodegenerative disorder. The load of neurofibrillary tangles correlates strongly with clinical progression of the disease. Although tauopathy has been extensively studied as a key hypothesis in AD, there are currently no clinical tau‐targeted drugs that produce a noticeable improvement. Therefore, we studied and developed novel tau‐targeted therapeutic drug candidates for the treatment of AD; in particular, tau aggregation inhibitors.MethodWe performed high‐content screening based on a Tau‐BiFC cell‐based assay platform and identified novel tau aggregation inhibitors. Lead optimization was subsequently performed to improve potency and ADME/Tox properties, resulting in the production of DA‐7503. In vivo efficacy of the candidate was validated by demonstration of memory impairment restoration in two transgenic animal models of P301L Tau‐BiFC and rTg4510. The non‐clinical GLP‐Tox studies of DA‐7503 is ongoing in order to proceed to clinical studies.ResultDA‐7503 exhibited excellent tau aggregation inhibitory activities (cell‐based IC50, 0.02 mM, in vitro IC50, 0.96 mM) with good cell viability (MTS IC50, 77.8 mM). DA‐7503 reduced tau oligomerization and protected against neuronal cell death. It restored memory impairment in P301L Tau‐BiFC and rTg4510 Tg mouse models (NOR, Open Field, and Morris Water Maze test) with reduction of tau pathology. The mode of action of DA‐7503 was confirmed by MALDI‐TOF Mass Spectrometric Analysis, 2D HSQC NMR and TR‐2 competition study to show reversible covalent inhibition of disulfide‐dependent oligomer formation.Conclusion DA‐7503, a highly potent inhibitor of tau aggregation, significantly improved memory impairment and reduced tau pathology in P301L Tau‐BiFC and rTg4510 Tg mouse models with good pharmacological properties. Currently, the GLP‐Tox safety profile of DA‐7503 as a non‐clinical candidate is being evaluated, and early results are promising enough to proceed to clinical studies.

Efficacy evaluation of a novel vectorized anti‐tau antibody, targeting a C‐terminal phospho‐tau epitope, using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies.

AbstractBackgroundAnti‐tau immunotherapy has become a promising therapy for Alzheimer’s disease (AD) and tauopathies. With the hypothesis that tau pathology spreads via cell‐to‐cell transmission, including trans‐synaptic propagation, success of anti‐tau immunotherapy relies, in part, on the identification of efficacious antibodies and their delivery to affected or vulnerable brain regions with sufficient or enhanced exposure in the CNS. We have previously demonstrated broad distribution and expression of vectorized anti‐tau antibodies in the mouse brain using a blood brain barrier penetrant capsid, VOY101, administered intravenously (IV).MethodSeveral novel anti‐tau antibodies that met the target profile have been generated and are being evaluated in vivo (Liu et al, submitted as a separated abstract in AAIC 2022).ResultOne of the antibodies discovered, antibody 1, exhibits strong affinity for PHF‐tau, demonstrates specific binding to tau pathology on brain sections of AD and PSP patients, and potently prevents PHF seeding and propagation in vitro and in vivo. This antibody recognizes a phospho‐specific epitope in the C‐terminal region of tau and shows significant reduction of tau pathology in an AD‐PHF induced P301S hippocampal seeding and propagation model. Furthermore, we have vectorized antibody 1 into an AAV expression vector with by BBB penetrant capsid and are evaluating it in two independent mouse models of tauopathy.ConclusionThis gene therapy‐based approach has potential advantages over traditional passive immunization, including 1) continuous expression of antibody in the central nervous system (CNS) after a single gene therapy administration compared to repetitive administrations of high dose of antibody by passive immunotherapy; 2) increased CNS exposure of tau antibody relative to passive immunotherapy; and 3) the potential to target intracellular tau aggregates which are less effectively accessed by passively delivered antibody. These results add to accumulating evidence that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.

Targeted Musashi1 knockdown leads to reduce tau pathology and improves cognitive function in aged P301L mouse model

AbstractBackgroundThe buildup of toxic tau species in the brain is thought to lead to the development of Alzheimer’s disease. While our current understanding of the mechanisms underlying this aggregation is limited, growing evidence has pointed to RNA‐binding proteins (RBPs) playing a role. The dysregulation of RBPs is associated with various neurodegenerative diseases. For example, during amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD), dysregulated TDP‐43 accumulates in the brain. Similarly, our recent studies showed that the RBP, Musashi‐1 (MSI1), may co‐aggregate with toxic tau oligomers in Alzheimer’s disease. Clarifying the connection between these two proteins may provide novel insights into the mechanisms behind toxic tau buildup in Alzheimer’s, allowing for new therapeutic targets in treatment development.MethodIn this study, we investigated the role of MSI1 on the aggregation and deposition of tau in aged (18‐months old) P301L mouse models, which express the P301L mutant form of tau. MSI1 expression was knocked down (KD) by performing intracerebroventricular injections of MSI1 antisense oligonucleotides into the hippocampus. The effects of MSI1 KD on tau accumulation and pathology were studied in the hippocampus, cortex, and cerebellum.ResultWestern blot and immunofluorescence (IF) analysis revealed a significant reduction in MSI1 and tau proteins levels and aggregation in the P301L mouse brain, mainly in the hippocampus. Furthermore, brain Co‐IF microscopy and Dot Blot analysis of the PBS‐ and Sarkosyl‐soluble fractions showed that there was a significant reduction of MSI1 and tau oligomeric species in the hippocampus, cortex, and cerebellum in MSI1 KD mice. In addition, phosphorylated tau forms (pSer422, pSer202/Thr205, pThr212/Ser214 and pThr231/Ser235) were significantly decreased in the cortex, cerebellum, and most prominently, in the hippocampus. Increase in synaptic marker Synaptophysin suggesting an increase of synaptogenesis. Behavioral tests, Novel Object Recognition (NOR) and Y‐Maze spontaneous alternations tests, MSI1‐KD mice showed significant improvements.ConclusionThese results suggest that MSI1 plays a major role in tau toxicity, revealing it as a possible target for treating Alzheimer’s disease.

Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy.

Emerging evidence from Alzheimer's disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology. Recently, we identified protopine as a dibenzazecine alkaloid with anti-HDAC6 and anti-AD activities. In this study, we synthesized and tested novel protopine derivatives for their pharmacological action against AD. Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models. Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of -8.4kcal/mol and an IC50 value of 1.51µM. In neuronal cell lines, PRO-Br reduced pathological tau by inducing chaperone-mediated autophagy (CMA). In 3xTg-AD and P301S tau mice models, PRO-Br specifically decreased the pathogenic hyperphosphorylated tau clumps and led to the restoration of memory functions. In addition, PRO-Br treatment promoted the clearance of pathogenic tau by enhancing the expression of molecular chaperones (HSC70) and lysosomal markers (LAMP2A) via CMA in AD models. Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD.

Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain

In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology. Our results show that dosing animals twice per week with PQR530 resulted in intermittent, rather than sustained target engagement. Nevertheless, this pulse-like mTOR inhibition followed by longer intervals of re-activation was sufficient to reduce tau pathology in the cerebral cortex in P301S tau transgenic mice. This suggests that balanced therapeutic dosing of blood-brain-barrier permeable mTOR-inhibitors can result in a disease-modifying effect in AD and at the same time prevents toxic side effects due to prolonged over activation of autophagy.

Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy.

Tau-specific immunotherapy is an attractive strategy for the treatment of Alzheimer's disease and other tauopathies. However, effectively targeting tau in the brain remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes an estimated >99% of peripherally administered antibodies. However, their transport across the BBB can be facilitated by a novel modality, low-intensity scanning ultrasound used in combination with intravenously injected microbubbles (SUS+MB). We have previously shown that SUS+MB-mediated delivery of a tau-specific antibody in a single-chain (scFv) format to tau transgenic mice enhanced brain and neuronal uptake and subsequently, reduced tau pathology and improved behavioural outcomes to a larger extent than either scFv or SUS+MB on its own. Here we generated a novel tau-specific monoclonal antibody, RNF5, and validated it in its IgG format in the presence or absence of SUS+MB by treating K369I tau transgenic K3 mice once weekly for 12weeks. We found that both RNF5 and SUS+MB treatments on their own significantly reduced tau pathology. In the combination group (RNF5+SUS+MB), however, despite increased antibody localization in the brain, there were no further reductions in tau pathology when compared to RNF5 treatment alone. Furthermore, following SUS+MB, RNF5 accumulated heavily within cells across the pyramidal cell layer of the hippocampus, that were negative for MAP2 and p-tau, suggesting that SUS+MB may not facilitate enhanced RNF5 engagement of intraneuronal tau. Overall, our new findings reveal the complexities of combining tau immunotherapy with SUS+MB and challenge the view that this is a straight-forward approach.

Single‐molecule imaging reveals Tau trapping at nanometer‐sized dynamic hot spots near the plasma membrane that persists after microtubule perturbation and cholesterol depletion

Accumulation of aggregates of the microtubule‐binding protein Tau is a pathological hallmark of Alzheimer's disease. While Tau is thought to primarily associate with microtubules, it also interacts with and localizes to the plasma membrane. However, little is known about how Tau behaves and organizes at the plasma membrane of live cells. Using quantitative, single‐molecule imaging, we show that Tau exhibits spatial and kinetic heterogeneity near the plasma membrane of live cells, resulting in the formation of nanometer‐sized hot spots. The hot spots lasted tens of seconds, much longer than the short dwell time (∼ 40 ms) of Tau on microtubules. Pharmacological and biochemical disruption of Tau/microtubule interactions did not prevent hot spot formation, suggesting that these are different from the reported Tau condensation on microtubules. Although cholesterol removal has been shown to reduce Tau pathology, its acute depletion did not affect Tau hot spot dynamics. Our study identifies an intrinsic dynamic property of Tau near the plasma membrane that may facilitate the formation of assembly sites for Tau to assume its physiological and pathological functions.

Late-Life Obesity Associated with Tau Pathology in Cognitively Normal Individuals: The CABLE Study.

Existed evidence suggests that midlife obesity increases the risk of Alzheimer's disease (AD), while there is an inverse association between AD and obesity in late life. However, the underlying metabolic changes of AD pathological proteins attributed to obesity in two life stages were not clear. To investigate the associations of obesity types and obesity indices with AD biomarkers in cerebrospinal fluid (CSF) in different life stages. We recruited 1,051 cognitively normal individuals (61.94±10.29 years, 59.66%male) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF detections for amyloid-β 42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau). We utilized body mass index, waist circumference, waist-to-height ratio, and metabolic risk factors to determine human obesity types. Multiple linear models and interaction analyses were run to assess the impacts of obesity on AD biomarkers. The metabolically unhealthy obesity or healthy obesity might exert a reduced tau pathology burden (p < 0.05). Individuals with overweight, general obesity, and central obesity presented lower levels of tau-related proteins in CSF than normal controls (p < 0.05). Specially, for late-life individuals, higher levels of obesity indices were associated with a lower load of tau pathology as measured by CSF T-tau and T-tau/Aβ42 (p < 0.05). No similar significant associations were observed in midlife. Collectively, late-life general and central obesity seems to be associated with the reduced load of tau pathology, which further consolidates the favorable influence of obesity in specific life courses for AD prevention.

Efficacy of a vectorized anti‐tau antibody using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies

AbstractBackgroundAnti‐tau immunotherapy is a promising therapy for tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). While passive immunization with anti‐tau monoclonal antibodies has been shown by several laboratories to reduce age‐dependent tau pathology and neurodegeneration in mouse tauopathy models, these studies have typically used repeated high weekly doses of antibody and reported only moderate reduction of tau pathology. To circumvent these limitations, using an adeno‐associated virus (AAV) vector to deliver a tau monoclonal antibody into hippocampus by direct injection to the location have been described. High levels of antibody and marked reduction of tau pathology is achieved by this approach. To further optimize this approach with a lesser invasive administration route, we have previously demonstrated broad distribution and expression of a vectorized anti‐tau antibody in the mouse brain using a blood‐brain barrier (BBB) penetrant AAV capsid administered intravenously (IV). This gene therapy‐based approach has potential advantages, including continuous expression of antibody in the central nervous system (CNS) after a single administration of vector, increased CNS levels of tau antibody relative to passive immunotherapy, and the potential to target intracellular tau aggregates. Here we describe studies characterizing the onset of transduction following dosing with a vectorized tau antibody and its efficacy in mouse models of tauopathy.MethodAAV vectors comprising the BBB‐penetrant AAV capsid and a transgene encoding an anti‐tau monoclonal antibody were administered by IV bolus to mouse models of tauopathy. Biodistribution and cellular tropism in the CNS were evaluated by ELISA and (or) immunostaining. Tau pathology was measured by AT100 immunohistochemistry and AT8 ELISA.ResultWe then investigated efficacy in reduction of tau pathology in mouse tauopathy models. Treatment with our vectorized antibody resulted in durable antibody expression in the CNS and a corresponding reduction in CNS insoluble pathological tau and neurofibrillary tangles.ConclusionOur results indicate that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.

Targeting aggregated tau turnover as a therapeutic strategy

The accumulation of microtubule-associated protein tau in intracellular inclusions is a common feature of Alzheimer's disease and other tauopathies. We have recently identified using optical pulse labelling methodology (OPL) that neurofibrillary tau inclusions comprised of aggregated tau are dynamic structures that show turnover of aggregated tau. This occurs in both intrinsically formed and exogenously seeded tau inclusions. Understanding the mechanisms by which this turnover occurs could inform how to most appropriately treat tauopathies.Using recombinant adeno-associated viruses (rAAVs) we are able to deliver Dendra2-tagged pro-aggregant and non-aggregating tau to murine brain slice cultures with and without the application of exogenous tau seeds. These methods facilitate the long-term tracking of tau inclusion dynamics using OPL methodology. In combination with these methods, we can begin to assess whether compounds, monoclonal antibodies or other potential therapeutic modulators change tau aggregate turnover or affect tau by differential mechanisms.Using OPL, we can track the formation of neurofibrillary tau inclusions and the kinetics of tau turnover. We find that newly formed tau inclusions show turnover, but with ageing in culture the rate of turnover slows. Using this experimental paradigm, we now aim to begin to understand the mechanisms that facilitate this turnover and determine whether therapies that affect this turnover may be beneficial. We also find that a compound known to reduce tau pathology reduces tau phosphorylation and tau insolubility but does not affect the rate of tau production or clearance.Our OPL studies have documented that neurofibrillary tau inclusions comprised of aggregated tau show daily turnover of tau, at least when initially formed. We now aim to use this system to begin to understand the cellular processes that facilitate this tau inclusion turnover. Furthermore, understanding these mechanisms may lead to new therapeutic strategies for Alzheimer's disease and other neurodegenerative conditions where tau plays a role.

Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway.

SUMMARYPathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.

Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation.

Repair after traumatic injury often starts with mitotic activation around the lesion edges. Early midline cells in the Drosophila embryonic CNS can enter into division following the traumatic disruption of microtubules. We demonstrate that microtubule disruption activates non-canonical TNF signaling by phosphorylation of TGF-β activated kinase 1 (Tak1) and its target IkappaB kinase (Ik2), culminating in Dorsal/NfkappaB nuclear translocation and Jra/Jun expression. Tak1 and Ik2 are necessary for the damaged-induced divisions. Microtubule disruption caused by Tau accumulation is also reported in Alzheimer's disease (AD). Human Tau expression in Drosophila midline cells is sufficient to induce Tak1 phosphorylation, Dorsal and Jra/Jun expression, and entry into mitosis. Interestingly, activation of Tak1 and Tank binding kinase 1 (Tbk1), the human Ik2 ortholog, and NfkappaB upregulation are observed in AD brains.

LDL receptor upregulation reduces tau pathology.

LDL receptor upregulation reduces tau pathology.

Antisense Oligonucleotide-Mediated Reduction of HDAC6 Does Not Reduce Tau Pathology in P301S Tau Transgenic Mice.

Acetylation of tau protein is dysregulated in Alzheimer's Disease (AD). It has been proposed that acetylation of specific sites in the KXGS motif of tau can regulate phosphorylation of nearby residues and reduce the propensity of tau to aggregate. Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme involved in deacetylation of multiple targets, including tau, and it has been suggested that inhibition of HDAC6 would increase tau acetylation at the KXGS motifs and thus may present a viable therapeutic approach to treat AD. To directly test the contribution of HDAC6 to tau pathology, we intracerebroventricularly injected an antisense oligonucleotide (ASO) directed against HDAC6 mRNA into brains of P301S tau mice (PS19 model), which resulted in a 70% knockdown of HDAC6 protein in the brain. Despite a robust decrease in levels of HDAC6, no increase in tau acetylation was observed. Additionally, no change of tau phosphorylation or tau aggregation was detected upon the knockdown of HDAC6. We conclude that HDAC6 does not impact tau pathology in PS19 mice.

Plexin-A4 mediates amyloid-β-induced tau pathology in Alzheimer's disease animal model.

Amyloid-β (Aβ) and tau are major pathological hallmarks of Alzheimer's disease (AD). Several studies have revealed that Aβ accelerates pathological tau transition and spreading during the disease progression, and that reducing tau can mitigate pathological features of AD. However, molecular links between Aβ and tau pathologies remain elusive. Here, we suggest a novel role for the plexin-A4 as an Aβ receptor that induces aggregated tau pathology. Plexin-A4, previously known as proteins involved in regulating axon guidance and synaptic plasticity, can bound to Aβ with co-receptor, neuropilin-2. Genetic downregulation of plexin-A4 in neurons was sufficient to prevent Aβ-induced activation of CDK5 and reduce tau hyperphosphorylation and aggregation, even in the presence of Aβ. In an AD mouse model that manifests both Aβ and tau pathologies, genetic downregulation of plexin-A4 in the hippocampus reduced tau pathology and ameliorated spatial memory impairment. Collectively, these results indicate that the plexin-A4 is capable of mediating Aβ-induced tau pathology in AD pathogenesis.

Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer's Disease.

Background:Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD.Objective:Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred.Methods:Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method.Results:Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques.Conclusion:These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.

Tau antibody isotype induces differential effects following passive immunisation of tau transgenic mice

One of the main pathological hallmarks of Alzheimer’s disease (AD) is the intraneuronal accumulation of hyperphosphorylated tau. Passive immunotherapy is a promising strategy for the treatment of AD and there are currently a number of tau-specific monoclonal antibodies in clinical trials. A proposed mechanism of action is to engage and clear extracellular, pathogenic forms of tau. This process has been shown in vitro to be facilitated by microglial phagocytosis through interactions between the antibody-tau complex and microglial Fc-receptors. As this interaction is mediated by the conformation of the antibody's Fc domain, this suggests that the antibody isotype may affect the microglial phagocytosis and clearance of tau, and hence, the overall efficacy of tau antibodies. We therefore aimed to directly compare the efficacy of the tau-specific antibody, RN2N, cloned into a murine IgG1/κ framework, which has low affinity Fc-receptor binding, to that cloned into a murine IgG2a/κ framework, which has high affinity Fc-receptor binding. Our results demonstrate, for RN2N, that although enhanced microglial activation via the IgG2a/κ isotype increased extracellular tau phagocytosis in vitro, the IgG1/κ isoform demonstrated enhanced ability to reduce tau pathology and microgliosis following passive immunisation of the P301L tau transgenic pR5 mouse model.