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- W2336305416 abstract "The mechanisms underlying the abnormal phosphorylation and accumulation of tau in AD remain unclear, but one of the possibilities is that it might be due to conformational changes in tau in the diseased brain. Anti-tau immunotherapy has recently emerged as a promising approach to target tau, but many mechanistic questions regarding the optimal form of anti-tau immunotherapy remain. We hypothesize that anti-tau immunotherapy may be optimized by targeting both intracellular and extracellular pools of tau and that specific binding of hyperphosphorylated tau by single chain variable fragments (scFv) or by intracellularly expressed intrabodies will prevent its toxicity and formation of neurofibrillary tangles. We cloned scFvs from two monoclonal anti-phospho-Tau antibodies (PHF and CP13) and generated stable intracellular anti-Ptau scFvs (intrabodies), as well as scFvs, directed into the secretory pathway. Then we expressed these intrabodies and scFvs in the brains of newborn transgenic rTg4510 mice and in spinal cords of homozygous JNPL p301L mice. Effects on pathology and life expectancy were assessed at three, six and 12 month of age. Analysis of three month old rTg4510 brains revealed that both intrabodies and scFvs attenuated tau pathology relative to PBS-injected controls with CP13i being the most effective. Similarly, CP13i as well as PHFi significantly prolonged life expectancy of homozygous JNPL P301L mice and reduced accumulation of phosphorylated Tau in the spinal cords of 6 month old presymtomatic mice. Furthermore, we are assessing effects of funcionalized intrabodies, targeted to specific cellular compartments, on development of Tau pathology. These studies suggest that targeting phosphorylated tau in the intracellular vs. extracellular compartment is feasible therapeutic approach against tauopathy in animal models, and addition of functional aspect to the intrabody may increase its therapeutic ability." @default.
- W2336305416 created "2016-06-24" @default.
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- W2336305416 date "2015-07-01" @default.
- W2336305416 modified "2023-09-27" @default.
- W2336305416 title "O3-04-06: Functionalized intrabodies as potential tau targeting therapy" @default.
- W2336305416 doi "https://doi.org/10.1016/j.jalz.2015.07.259" @default.
- W2336305416 hasPublicationYear "2015" @default.
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