Premium
P3‐323: Early BDNF gene delivery into entorhinal cortex in APP transgenic mice ameliorates cells loss and preserves context‐dependent fear conditioning
Author(s) -
Nagahara Alan H.,
Mateling Michael,
Eggert Simone,
Blesch Armin,
Rockenstein Edward,
Koo Edward H.,
Masliah Eliezer,
Tuszynski Mark H.
Publication year - 2010
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.2010.05.1824
Subject(s) - entorhinal cortex , dentate gyrus , fear conditioning , context (archaeology) , neuroscience , hippocampus , synaptic plasticity , brain derived neurotrophic factor , water maze , neurotrophic factors , psychology , biology , medicine , amygdala , receptor , paleontology
last dose, to assess Ab and compound levels in these compartments. Plasma samples were also collected on Day 1 and interim timepoints throughout the studies. For single-dose timecourse studies, a single dose of ELND006 or vehicle was orally administered to lumbar cannulated cynomolgus monkeys using a crossover design. CSF and blood samples were collected and evaluated for ELND006 and Ab concentrations at predose and various timepoints post dose. Compound levels were determined by LC-MS/MS. Ab levels (1-x, x40 or x-42) were determined by ELISA. Results: In a 13-week repeat-dose study with ELND006, brain Ab in the cynomolgus monkey was decreased at least 25% for approximately 24 hours/day at 0.3 mg/kg/day of ELND006. Good brain penetration was observed, with brain:plasma ratios (Kp) greater than 1. Plasma ELND006 concentrations required to achieve 25% reduction in brain and CSF Ab were estimated to be 8 ng/mL and 65 ng/mL, respectively. The plasma concentrations required to achieve 25% reduction in CSF Ab from repeat-dose studies were similar to those required to reduce CSF Ab in the cannulated monkey model. Treatment with a single dose of ELND006 resulted in rapid reduction of Ab in the plasma, with a subsequent overshoot above control values at later timepoints, consistent with results reported following treatment with other gamma-secretase inhibitors. Conclusions: Brain, CSF and plasma Ab levels obtained from single-dose and repeat-dose cynomolgus monkey studies allow for effective assessment of exposure-response relationships in the monkey. These studies demonstrated that ELND006 penetrates the CNS of nonhuman primates and reduces Ab levels in a dose dependent manner.