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P1–386: Cross‐species analysis of cerebrospinal fluid (CSF) beta‐amyloid reductions by the BACE1 inhibitor PF‐05297909 indicates species differences in PK/PD relationships: Relevance to clinical translation
Author(s) -
HajosKorcsok Eva,
Nolan Charles,
Robshaw Ashley,
Christoffersen Curt,
Lu Yasong,
Chang Cheng,
Duvvuri Sridhar,
Brodney Michael,
O'Neill Brian,
Nicholas Timothy,
Bell Joanne,
Riddell David
Publication year - 2013
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.2013.05.613
Subject(s) - cerebrospinal fluid , pharmacodynamics , pharmacokinetics , cisterna magna , pharmacology , beta (programming language) , human brain , amyloid precursor protein secretase , medicine , chemistry , biology , endocrinology , amyloid precursor protein , alzheimer's disease , disease , computer science , programming language , psychiatry
reversed Ab oligomer-damaged long-term potentiation (LTP) at concentrations that did not interfere normal high frequency stimulation-induced LTP. Moreover, bis(heptyl)-cognitin prevented Ab oligomer-induced reduction of neurite length and synaptic quantity in mature hippocampal neurons. In contrast, tacrine could not reverse synaptic impairments in these models. Under oligomerization condition, bis(heptyl)-cognitin reduced the amount of Ab oligomer as evidenced by dot blot assay and immunoblot analysis. Finally, bis(heptyl)-cognitin was shown to alter Ab self-assembling as demonstrated by circular dichroism spectroscopy and transmission electron microscopy. Conclusions: All these results not only offer a modality as to how dimeric agents protect against Ab oligomer-induced synaptic impairments, but also offers a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.