Anti-tau Monoclonal Antibody Research Articles

Comparative the efficacy and safety of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in patients with Alzheimer’s disease: a systematic review and network meta-analysis of randomized controlled trials

ObjectiveThe aim of this study was to compare the efficacy and safety of anti-tau protein monoclonal antibodies for Alzheimer’s disease (AD). Tau protein aggregation, a key pathological feature of AD, is closely associated with neurodegeneration and cognitive decline. Targeting tau protein has emerged as a promising therapeutic strategy. By investigating the effects of monoclonal antibodies on cognitive function, disease progression, and overall quality of life in patients with AD, which can provide valuable insights into their potential as a therapeutic option for this devastating neurodegenerative disorder.MethodsThe randomized controlled trials (RCTs) investigating the efficacy of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in Alzheimer’s disease (AD) were systematically searched across PubMed, Embase, Web of Science and Cochrane Library, up to May 2024. The control group included placebo. The efficacy indicators were change in the Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) from baseline until the time of efficacy observation. Statistical analysis was conducted using Stata 14 and RevMan 5.4. The purpose of data processing, including generating network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots, and funnel plots, is to visually summarize and evaluate the relative effectiveness and safety and potential publication bias of multiple interventions. Mean differences (MD) and 95% confidence interval (95%CI) as effect sizes to analyze continuous variables.ResultsThis study encompassed six RCTs involving 2,193 patients. Semorinemab were more effective than placebo in MMSE and ADAS-Cog scores (MDs ranging between 0.52 and 3.21; MDs ranging between 0.17 and 3.30). Placebo showed relatively good efficacy according to SUCRA ranking on change in CDR-SB and ADCS-ADL scores (75.7 and 79.5%). Tilavonemab and Semorinemab exhibited efficacy similar to that of a placebo in the analysis of the two indicators. Tilavonemab showed a lower incidence of AE, SAE, fall, and urinary tract infections than placebo, and the differences were statistically significant. Most safety analysis results showed no statistical difference.ConclusionThe results indicated that anti-tau protein monoclonal antibodies, such as Semorinemab and Tilavonemab, showed promise in terms of efficacy and safety for managing AD. Further studies are needed to confirm these findings, assess long-term effects, and refine treatment protocols.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#myprospero, CRD42024583388.

Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology.

Semorinemab, an anti-tau monoclonal antibody, was assessed in two Phase II trials for Alzheimer's disease (AD). Plasma and cerebrospinal fluid (CSF) biomarkers provided insights into the drug's potential mechanism of action. Qualified assays were used to measure biomarkers of tau, amyloidosis, glial activity, neuroinflammation, synaptic function, and neurodegeneration from participant samples in Tauriel (NCT03289143) and Lauriet (NCT03828747) Phase II trials. Plasma phosphorylated Tau 181 (pTau181) and CSF chitinase-3-like protein 1 (YKL-40) increased following semorinemab treatment in both studies. In Lauriet, increasing plasma glial fibrillary protein (GFAP) concentrations stabilized with semorinemab, while this was not observed in Tauriel. Other AD pathophysiology biomarkers showed no consistent response to semorinemab. Increases in CSF YKL-40 suggest that semorinemab may stimulate microglia activation in the presence of AD-associated Tau pathology, but not in healthy controls. Stabilization of plasma GFAP in Lauriet indicates a possible impact on reactive gliosis in mild-to-moderate AD. Tauriel ClinicalTrials.gov Identifier: NCT03289143. Lauriet ClinicalTrials.gov Identifier: NCT03828747. Phase 1 ClinicalTrials.gov Identifier: NCT02820896. AD pathophysiology biomarkers were measured to assess the mechanism of action. Semorinemab increased CSF YKL-40 in participants with AD but not in healthy controls. Semorinemab possibly stabilized plasma GFAP in the Lauriet trial. Semorinemab treatment may activate microglia and moderate reactive gliosis.

Phase 1 Studies of the Anti-Tau Monoclonal Antibody JNJ-63733657 in Healthy Participants and Participants with Alzheimer’s Disease

BackgroundJNJ-63733657 (posdinemab) is a humanized IgG1/kappa monoclonal anti-phospho tau antibody that binds with high affinity to phosphorylated amino acid 217 (pT217) in the proline-rich domain. The parent molecule, PT3, was raised against Alzheimer’s disease brain purified paired helical filament, and preclinical studies with the humanized version, JNJ-63733657, have demonstrated reductions in tau seeding. The results of the first-in-human clinical trial of JNJ-63733657 and a separate single ascending dose study in Japanese participants are presented.ObjectivesTo evaluate the safety and tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of JNJ-63733657 after single and multiple intravenous dose administrations in healthy participants and participants with prodromal or mild Alzheimer’s disease.DesignA two part first-in-human, phase 1, randomized, double-blind, placebo-controlled trial: Single ascending dose (Part 1) and multiple ascending dose (Part 2). And a phase 1, randomized, double-blind, placebo-controlled single ascending dose trial in healthy Japanese participants.Setting7 sites in Belgium, Netherlands, Spain, and Germany; 1 site in Japan.ParticipantsA total of 40 healthy participants aged 55–75 were enrolled in Part 1 of the first-in-human study; a total of 16 healthy participants and 13 participants with prodromal or mild AD aged 55–80 years were enrolled in Part 2. In the Japanese trial, a total of 24 participants aged 55–75 were enrolled.InterventionIn Part 1, single doses of 1, 3, 10, 30, or 60 mg/kg of JNJ-63733657 or placebo were administered to healthy participants. In Part 2, two dose levels of JNJ-63733657 (5 mg/kg or 50 mg/kg) or placebo were evaluated in healthy participants, and 2 dose levels (15 mg/kg or 30 mg/kg) or placebo were evaluated in participants with Alzheimer’s disease; doses were administered on Days 1, 29, and 57. In the Japanese trial, single doses of 3, 15, or 60 mg/kg of JNJ-63733675 or placebo were administered. All doses were administered intravenously.MeasurementsSafety assessments, serum and cerebrospinal fluid pharmacokinetic parameters, immunogenicity, and cerebrospinal fluid pharmacodynamic changes in free and total p217+tau, total tau, and p181tau were evaluated.ResultsJNJ-63733657 was generally safe and well-tolerated in healthy participants and participants with Alzheimer’s disease. In healthy participants and participants with Alzheimer’s disease, JNJ-63733657 demonstrated linear PK, and serum Cmax and AUC were approximately dose proportional following single and multiple doses. Dose-dependent reductions in free and total p217+tau in cerebrospinal fluid were observed. No changes in total tau or p181tau were observed in healthy participants whereas Alzheimer’s disease participants showed decreases in these tau species following administration of JNJ-63733657.ConclusionIn these Phase 1 trials, no safety or tolerability concerns were identified, and dose dependent reductions in p217+tau in the cerebrospinal fluid were demonstrated following administration of JNJ-63733657. The safety and biomarker profiles support the continued investigation of this compound for the slowing of disease progression in Alzheimer’s disease.

Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins.

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick's disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Novel ultrasensitive immunoassay for the selective quantification of tau oligomers and related soluble aggregates.

Tau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier-stage tau aggregates are lacking. We describe an immunoassay that is selective for tau oligomers and related soluble aggregates over monomers. A homogeneous (single-antibody) immunoassay was developed using a novel anti-tau monoclonal antibody and validated with recombinant and brain tissue-derived tau. The assay signals were concentration dependent for recombinant tau aggregates in solution but not monomers, and recognized peptides within, but not outside, the aggregation-prone microtubule binding region. The signals in inferior and middle frontal cortical tissue homogenates increased with neuropathologically determined Braak staging, and were higher in insoluble than soluble homogenized brain fractions. Autopsy-verified AD gave stronger signals than other neurodegenerative diseases. The quantitative oligomer/soluble aggregate-specific assay can identify soluble tau aggregates, including oligomers, from monomers in human and in vitro biospecimens. The aggregation of tau to form fibrils and neurofibrillary tangles is a key feature of Alzheimer's disease. However, biochemical assays for the quantification of oligomers/soluble aggregated forms of tau are lacking. We developed a new assay that preferentially binds to soluble tau aggregates, including oligomers and fibrils, versus monomers. The assay signal increased corresponding to the total protein content, Braak staging, and insolubility of the sequentially homogenized brain tissue fractions in an autopsy-verified cohort. The assay recognized tau peptides containing the microtubule binding region but not those covering the N- or C-terminal regions only.

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer’s disease

In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO (NCT03352557), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab—a monoclonal antibody to N-terminal tau—in patients with early Alzheimer’s disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

Development and Characterization of Mouse-Specific Anti-Tau Monoclonal Antibodies: Relevance for Analysis of Murine Tau in Cerebrospinal Fluid.

Clearance of tau seeds by immunization with tau antibodies is currently evaluated as therapeutic strategy to block the spreading of tau pathology in Alzheimer's disease and other tauopathies. Preclinical evaluation of passive immunotherapy is performed in different cellular culture systems and in wild-type and human tau transgenic mouse models. Depending on the preclinical model used, tau seeds or induced aggregates can either be of mouse, human or mixed origin. We aimed to develop human and mouse tau-specific antibodies to discriminate between the endogenous tau and the introduced form in preclinical models. Using hybridoma technology, we developed human and mouse tau-specific antibodies that were then used to develop several assays to specifically detect mouse tau. Four antibodies, mTau3, mTau5, mTau8, and mTau9, with a high degree of specificity for mouse tau were identified. Additionally, their potential application in highly sensitive immunoassays to measure tau in mouse brain homogenate and cerebrospinal fluid is illustrated, as well as their application for specific endogenous mouse tau aggregation detection. The antibodies reported here can be very important tools to better interpret the results obtained from different model systems as well as to study the role of endogenous tau in tau aggregation and pathology observed in the diverse mouse models available.

Chapter 31 - Passive tau-based immunotherapy for tauopathies

Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. In secondary tauopathies, i.e., Alzheimer's disease (AD), tau deposition can be observed, but tau may coexist with another protein, i.e., amyloid-β. In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. Treatments are being developed to interfere with the aggregation process or to promote the clearance of tau protein. Several tau-targeted passive immunotherapy approaches are in development for treating tauopathies. At present, 12 anti-tau antibodies have entered clinical trials, and 7 of them are still in clinical testing for primary tauopathies and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, PNT00, and APNmAb005). However, none of these seven agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Two other anti-tau monoclonal antibodies have been discontinued for the treatment of primary tauopathies, i.e., gosuranemab and tilavonemab. Further evidence will come from ongoing Phase I/II trials on passive immunotherapeutics for treating primary and secondary tauopathies.

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

Tau cleavage plays a crucial role in the onset and progression of Alzheimer’s Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)—a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance—mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it’s in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.

A critical appraisal of tau-targeting therapies for primary and secondary tauopathies.

Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti-tau monoclonal antibodies have not shown clinical efficacy. The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non-specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and post-translational tau modifications.

Comparison of size distribution and (Pro249-Ser258) epitope exposure in in vitro and in vivo derived Tau fibrils

BackgroundAlthough several studies demonstrate prion-like properties of Tau fibrils, the effect of size in the seeding capacity of these aggregates is not fully understood. The aim of this study is to characterize Tau seeds by their size and seeding capacity.MethodsTau aggregates were isolated from postmortem AD brain tissue and separated from low molecular weight species by sucrose gradient ultracentrifugation. Biochemical characterization of the different fractions was done by non-reducing Western blotting and aggregate-specific immuno-assays using in house developed anti-Tau monoclonal antibodies, including PT76 which binds to an epitope close to the microtubule-binding domain and, hence, also to K18. Seeding efficiency was then assessed in HEK293 cells expressing K18 FRET sensors.ResultsWe observed that upon sonication of Tau aggregates different size-distributed tau aggregates are obtained. In biochemical assays, these forms show higher signals than the non-sonicated material in some aggregation-specific Tau assays. This could be explained by an increased epitope exposure of the smaller aggregates created by the sonication. By analyzing human brain derived and recombinant (K18) Tau aggregates in a cellular FRET assay, it was observed that, in the absence of transfection reagent, sonicated aggregates showed higher aggregation induction. Preparations also showed altered profiles on native PAGE upon sonication and we could further separate different aggregate species based on their molecular weight via sucrose gradients.ConclusionsThis study further elucidates the molecular properties regarding relative aggregate size and seeding efficiency of sonicated vs. non-sonicated high molecular weight Tau species. This information will provide a better knowledge on how sonication, a commonly used technique in the field of study of Tau aggregation, impacts the aggregates. In addition, the description of PT76-based aggregation specific assay is a valuable tool to quantify K18 and human AD Tau fibrils.

Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer\u2019s disease

BackgroundThe spread of tau pathology in Alzheimer’s disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo.MethodsWe inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs.ResultsDMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044.ConclusionsThese findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.

Plasma Tau Variants Detected by a Novel Anti-Tau Monoclonal Antibody: A Potential Biomarker for Alzheimer's Disease.

A major drawback in Alzheimer's disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau®, based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. To analyze a potential novel source of antigen for Alz-tau®, plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by western blot with this novel monoclonal antibody. The HMW/LMWtau ratio was statistically different between AD patients and controls. Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD.

Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial

Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. Bristol-Myers Squibb, Biogen.

Cellular Prion Protein Mediates the Disruption of Hippocampal Synaptic Plasticity by Soluble Tau In Vivo.

Intracellular neurofibrillary tangles (NFTs) composed of tau protein are a neuropathological hallmark of several neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). For some time NFTs were considered the primary cause of synaptic dysfunction and neuronal death, however, more recent evidence suggests that soluble aggregates of tau are key drivers of disease. Here we investigated the effect of different tau species on synaptic plasticity in the male rat hippocampus in vivo Intracerebroventricular injection of soluble aggregates formed from either wild-type or P301S human recombinant tau potently inhibited hippocampal long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, tau monomers and fibrils appeared inactive. Neither baseline synaptic transmission, paired-pulse facilitation nor burst response during high-frequency conditioning stimulation was affected by the soluble tau aggregates. Similarly, certain AD brain soluble extracts inhibited LTP in a tau-dependent manner that was abrogated by either immunodepletion with, or coinjection of, a mid-region anti-tau monoclonal antibody (mAb), Tau5. Importantly, this tau-mediated block of LTP was prevented by administration of mAbs selective for the prion protein (PrP). Specifically, mAbs to both the mid-region (6D11) and N-terminus (MI-0131) of PrP prevented inhibition of LTP by both recombinant and brain-derived tau. These findings indicate that PrP is a mediator of tau-induced synaptic dysfunction.SIGNIFICANCE STATEMENT Here we report that certain soluble forms of tau selectively disrupt synaptic plasticity in the live rat hippocampus. Further, we show that monoclonal antibodies to cellular prion protein abrogate the impairment of long-term potentiation caused both by recombinant and Alzheimer's disease brain-derived soluble tau. These findings support a critical role for cellular prion protein in the deleterious synaptic actions of extracellular soluble tau in tauopathies, including Alzheimer's disease. Thus, approaches targeting cellular prion protein, or downstream pathways, might provide an effective strategy for developing therapeutics.

Available and future treatments for atypical parkinsonism. A systematic review.

Success in treating patients with atypical parkinsonian syndromes, namely progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), multiple system atrophy (MSA), Parkinson's disease with dementia (PDD), and Lewy body dementia with (LBD), remains exceedingly low. The present work overviews the most influential research literature collected on MEDLINE, ISI Web of Science, Cochrane Library, and Scopus for available treatment in atypical parkinsonisms without time restriction. Transdermal rotigotine, autologous mesenchymal stem cells, tideglusib, and coenzyme Q10 along with donepezil, rivastigmine, memantine, and the deep brain stimulation have shown some benefits in alleviating symptoms in APS. Moreover, many new clinical trials are ongoing testing microtubule stabilizer, antitau monoclonal antibody, tau acetylation inhibition, cell replacement, selective serotonin reuptake inhibitor, active immunization, inhibition of toxic α-synuclein oligomers formation, and inhibition of microglia. A detailed knowledge of the pathological mechanism underlying the disorders is needed, and disease-modifying therapies are required to offer better therapeutic options to physician and caregivers of APS patients.

Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo.

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

What We Learn from the CTAD (Clinical Trials Alzheimer's Disease) 2018.

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aβ production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

Correction: Liu et al., "Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice".

Correction: Liu et al., "Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice".

A Simple Method to Avoid Nonspecific Signal When Using Monoclonal Anti-Tau Antibodies in Western Blotting of Mouse Brain Proteins.

In Alzheimer's disease and other tauopathies, tau displays several abnormal post-translation modifications such as hyperphosphorylation, truncation, conformation, and oligomerization. Mouse monoclonal antibodies have been raised against such tau modifications for research, diagnostic, and therapeutic purposes. However, many of these primary antibodies are at risk of giving nonspecific signals in common Western blotting procedures. Not because they are unspecific, but because the secondary antibodies used to detect them will also detect the heavy chain of endogenous mouse immunoglobulins (Igs), and give a nonspecific signal at the same molecular weight than tau protein (around 50 kDa). Here, we propose the use of anti-light chain secondary antibodies as a simple and efficient technique to prevent nonspecific Igs signals at around 50 kDa. We demonstrate the efficacy of this method by removing artifactual signals when using monoclonal antibodies directed at tau phosphorylation (AT100, 12E8, AT270), tau truncation (TauC3), tau oligomerization (TOMA), or tau abnormal conformation (Alz50), in wild-type, 3×Tg-AD, and tau knockout mice.