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Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease.

ABSTRACT: We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-beta polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on paired helical filaments from brains of AD patients and surface plasmon resonance studies confirm these findings. The capacity of these drugs to penetrate the blood-brain barrier was evaluated: i) in vitro by parallel artificial membrane permeability assay followed by experimental Log P determinations; and ii) in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain of mice using HPLC/UV. Importantly, our studies indicate that the brain/blood concentration ratios for these compounds were suitable for their use as PET radiotracers. Since neurofibrillary tangles are positively correlated with cognitive impairment, we concluded that LNS and AST have a great potential in PET neuroimaing for in vivo early detection of AD and in reducing the formation of neurofibrillary tangles.

SUBMITTER: Rojo LE

PROVIDER: S-EPMC2951486 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease.

Rojo Leonel E LE Alzate-Morales Jans J Saavedra Iván N IN Davies Peter P Maccioni Ricardo B RB

Journal of Alzheimer's disease : JAD 20100101 2

We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful ...[more]

PMID: 20110603

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Project description:Pathological tau aggregates in Alzheimer's disease (AD) and frontotemporal lobar degeneration-tau (FTLD-tau) adopt distinct conformations differentiated by the AD-tau specific monoclonal antibody (mAb) GT-38 that are not readily visualized using phosphorylation-specific anti-tau mAbs. To determine the extent of co-morbid AD-tau pathology in FTLD-tau, we performed immunohistochemical (IHC) staining with GT-38 and assigned Braak stages of AD-tau in a cohort 180 FTLD-tau cases consisting of corticobasal degeneration (CBD; n?=?49), progressive supranuclear palsy (PSP; n?=?109), and Pick's disease (PiD; n?=?22). Nearly two-thirds of patients (n?=?115 of 180, 63.8%) with FTLD-tau had some degree of comorbid AD-tau pathology and 20.5% of the FTLD-tau cohort had Braak stage ?B2, consistent with medium-to-high-level AD neuropathological change (ADNPC). The PSP group had the highest frequency of medium-high AD-tau pathology compared to other tauopathies (PSP?=?31/109, 28.4%; Picks?=?2/22, 9.1%, CBD?=?4/49, 8.2%) but neuropathological diagnosis was not found to be a significant independent predictor of medium-high AD Braak stage in a multivariate model after accounting for age at death (OR?=?1.09; 95% CI?=?1.03-1.15; p?=?0.002) and CERAD plaque scores (OR?=?3.75, 95% CI?=?1.58-8.89; p?=?0.003), suggesting there is no predilection for a specific FTLD tauopathy to develop AD-tau co-pathology after accounting for age. Patients with FTLD-tau who had, clinically significant, medium-high AD-tau pathology had significantly higher antemortem CSF levels of both total-tau (t-tau; mean?=?89.98?pg/ml, SD?=?36.70?pg/ml) and phosphorylated-tau (p-tau; mean?=?20.45?pg/ml, SD?=?9.31?pg/ml) compared to patients with negligible-low AD-tau, t-tau (mean?=?43.04?pg/ml, SD?=?25.40?pg/ml) and p-tau (mean?=?11.90?pg/ml, SD?=?4.48?pg/ml) (p???0.001 both). Finally, in an exploratory analysis in our largest pathology group (PSP) we find an association of GT-38?AD-tau Braak stage with lower baseline MMSE (p?=?0.03). Together, these finding validate the use of GT-38 to selectively detect AD-tau pathology in the context of FTLD-tau and provides a novel tool to investigate associations of clinical phenotypes amongst co-morbid tauopathies.

Project description: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.

Project description:We have identified structural determinants on tau protein that are essential for pathological tau-tau interaction in Alzheimer's disease (AD). These regulatory domains, revealed by monoclonal antibody DC8E8, represent a novel target for tau-directed therapy. In order to validate this target, we have developed an active vaccine, AADvac1.A tau peptide encompassing the epitope revealed by DC8E8 was selected for the development of an active vaccine targeting structural determinants on mis-disordered tau protein that are essential for pathological tau-tau interaction. The efficacy of the vaccine was tested in a transgenic rat model of human tauopathies. Toxicology and safety pharmacology studies were conducted under good laboratory practice conditions in multiple rodent and nonrodent species.We have administered the tau peptide vaccine to a rat model of AD to investigate whether the vaccine can improve its clinical, histopathological and biochemical AD phenotype. Our results show that vaccination induced a robust protective humoral immune response, with antibodies discriminating between pathological and physiological tau. Active immunotherapy reduced the levels of tau oligomers and the extent of neurofibrillary pathology in the brains of transgenic rats. Strikingly, immunotherapy has reduced AD-type hyperphosphorylation of tau by approximately 95%. Also, the tau peptide vaccine improved the clinical phenotype of transgenic animals. Toxicology and safety pharmacology studies showed an excellent safety and tolerability profile of the AADvac1 vaccine.Active immunisation targeting crucial domains of Alzheimer tau eliminated tau aggregation and neurofibrillary pathology. Most importantly, the AD type of tau hyperphosphorylation was abolished by vaccination across a wide range of AD phospho-epitopes. Our results demonstrate that active immunisation led to elimination of all major hallmarks of neurofibrillary pathology, which was reflected by a profound improvement in the clinical presentation of transgenic rats. This makes the investigated tau peptide vaccine a highly promising candidate therapeutic for the disease-modifying treatment of AD. The tested vaccine displayed a highly favourable safety profile in preclinical toxicity studies, which opens up the possibility of using it for AD prophylaxis in the future. The vaccine has already entered phase I clinical trial under the name AADvac1.Current Controlled Trials NCT01850238. Registered 7 May 2013.

Dataset Information

Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease.

Publications

Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease.

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