Tau oligomers have already been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimers disease (AD) and related tauopathies. the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from and cellular assays to an model of tau aggregation. studies showed both a good (S,R,S)-AHPC-PEG2-NH2 preliminary safety profile using pharmacology assays, a mini-Ames test, and CNS drug-like properties differentiating it from published TAI [32C35]. The aim of this study was to determine the efficacy of the lead compound in preventing the accumulation of tau aggregates in the htau mouse model best representing tau aggregation in AD. These studies were performed to validate the and cellular screening assays for selecting compounds and to further advance the lead compound toward preclinical development. MATERIALS AND METHODS Animals The htau mouse model of tauopathy expresses the six CNS isoforms of human tau protein under control of the human tau promoter and in place of endogenous murine tau [36]. There are no mutations in tau in this mouse model making htau an ideal model for studying the development of tau pathology in AD, as there are no mutations in tau associated with AD. For the primary study, 100 male and female mice were used, and in the confirmatory study 45 male htau mice were used. htau mice (Stock (S,R,S)-AHPC-PEG2-NH2 No: 005491) were ordered from The Jackson laboratory (Bar Harbor, Maine) and shipped to the Feinstein Institute for Medical Research (FIMR, Northwell Health, Manhasset, NY) where these were housed, analyzed and treated. For handles, tau knockout (KO) and JNPL3 mice had been purchased from Taconic Biosciences (Rensselaer, NY), and outrageous type C57/Bl6 through the (S,R,S)-AHPC-PEG2-NH2 Jackson Lab (Club Harbor, Maine). All experiments were in compliance using the FIMR Pet Use and Care Committee. Antibodies The antibodies found in these scholarly research had been all created, created, and formatted for assays in the lab of Peter Davies, Ph.D., Movie director, Litwin-Zucker Middle for Alzheimers Disease & Storage Disorders, The Feinstein Institute for Medical Analysis (Manhasset, NY). Pan-tau antibody mAb DA31 epitope spans proteins 150C190 in 4R2N tau [37]. Extra assays had been performed for phospho-tau epitopes important in Advertisement using antibodies PHF-1 (pSer-396/404) [38, 39], CP13 (pSer-202), [40, 41], RZ3 (pThr-231) [42], and MC1 that binds an AD-specific discontinuous epitope of tau, 7EFE9 and 313VDLSKVTSKC322 [43, 44]. Research design A precautionary research was performed dealing with mice from 2.5 to 6.5 months old using administration of compound in Rabbit Polyclonal to TTF2 feed. This allowed stress-free and harm-free administration in comparison to dental gavage or intraperitoneal injection for large numbers of mice for a relatively long study. One hundred mice were divided into four groups of mixed male and female mice that were treated with feed vehicle or feed formulated to provide a daily dose of 10, 40, or 100?mg/kg mouse. The dose was estimated using an average body weight of 25?g and an average daily consumption of 5?g of feed. The study was performed independently at The Feinstein Institute for Medical Research. The primary endpoint of the study was reduction of insoluble tau aggregates in the brains of the mice with statistical significance. The secondary endpoints were dose-dependent reduction of insoluble (S,R,S)-AHPC-PEG2-NH2 tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. To confirm the findings from the first study in the male mice, a second study was performed using a comparable approach in male htau mice. Three groups of male mice (and cellular assays to an model of tau aggregation. This validated our screening approach and exhibited (S,R,S)-AHPC-PEG2-NH2 that targeting tau self-association can inhibit the entire tau aggregation pathway. Studies are in progress to further address questions regarding whether the lead compound may have therapeutic efficacy, can ameliorate behavioral deficits, or have benefit for treating inherited forms of tauopathy. Preventive and therapeutic studies are being conducted in the JNPL3 mouse model of tauopathy that expresses the human tau 4R0N isoform with the mutation P301L associated with frontotemporal dementia. These mice.
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