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P4‐222: IN VIVO EFFICACY OF A SMALL MOLECULE INHIBITOR OF TAU OLIGOMER FORMATION IN HTAU MICE
Author(s) -
Moe James G.,
Lopez Patricia,
Jimenez Heidy,
Adrien Leslie,
Davies Peter,
Davidowitz Eliot J.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.07.043
Subject(s) - in vivo , tolerability , chemistry , pharmacology , toxicity , long term potentiation , pharmacokinetics , extracellular , tau protein , alzheimer's disease , biochemistry , medicine , adverse effect , biology , disease , receptor , microbiology and biotechnology , organic chemistry
Background:Recently, a panel of experts gathered by the National Institute of Aging and the Alzheimer’s Association published new biological guidelines for the definition of Alzheimer’s disease (AD) rather than the symptomatic approach typically used in the clinic. Such a change was judged necessary, considering that no FDA-approved AD treatments currently address the main hallmarks of the disease. With the recent clinical trial shortcomings of AD immunotherapy, gand b-secretase inhibitors, among other interventions, we and colleagues agree that a multifactorial approach is needed to address the polygenicity of AD. We used an epigenetic strategy where a single drug would simultaneously affect the expression of well-defined AD-related targets. Methods: AD-related genes and proteins were analyzed using NanoString technology, RT-qPCR methods, Western blots and ELISAs (N 1⁄4 3 to 6). Behavioral effects on the 3xTg AD mouse model were assessed using the open field, the Y-maze, the Barnes Maze and the novel object recognition tests (N1⁄410). Unpaired Student’s T-test was used whenever only two means were being compared. Oneway ANOVA or repeated measures two-way ANOVAwith appropriate post hoc analyses were used for multiple comparisons. Results:Pan and selective HDAC inhibition both reduce Ab(1-42) accumulation (p<0.05), decrease tau phosphorylation (p<0.01), and increase the expression of several high-priority AD-related protective genes. For example, compound M344 normalizes late-onset risk factor AD genes such as APOEe4 (p<0.0001) and BIN1 (p<0.0001). M344 also results in prevention of cognitive impairment in the 3xTg AD mice. M344 shows low toxicity, and rapidly clears out of brain and plasma. Similar positive results are also obtained with a more selective HDAC inhibitor compound. Conclusions:Our data suggest that brief daily brain exposure of a small epigenetic molecule can target the non-amyloidogenic pathway, increase neuroprotective genes, show low toxicity and increase memory in an AD model. This work supports a shift to a multitargeted approach to the treatment of AD.