[Abstract Title]. - Society for Neuroscience

the α-secretase product (s-APP-α) of amyloid precursor protein (APP) in AD skin fibroblasts
(N=4, for bryostatin: 289±67 (SEM); for picolog: 160±29 (SEM) with respect to 100 for control,
respectively). An autopsy-validated peripheral AD-Biomarker was also developed by our
laboratories (BRNI) based on bradykinin induced differential phosphorylation of Erk1 and Erk2.
Drug efficacy was tested using the AD-Biomarker as follows. Values of the AD-Biomarker (AD-
Index) were measured for control fibroblasts (Coriell Cell Repository) and were found to have
the negative (normal) values of the AD-Biomarker. After soluble amyloidogenic Aβ1-42 treatment
(1 κM, 16 hours), the fibroblasts were then found to have the AD-specific, positive AD-
Biomarker values (N=6, AD-Index changes from -0.057±0.030 (SEM) to +0.130±0.035 (SEM)).
Since the PKC activator, bryostatin, has shown both neuroprotective and cognitive enhancing
efficacy, we then tested the possibility that bryostatin might prevent the Aβ1-42-induced
abnormalities of the AD-Biomarker. Addition of 0.2 nM bryostatin protected against the Aβ1-42induced
change of the AD-Biomarker into the positive values that would have indicated the
presence of AD (see above). After bryostatin treatment, the AD-Index values returned back to
the normal lower values (AD-Index= -0.034±0.049 (SEM)) for control fibroblasts. Similar
results were obtained after picolog treatment. Both bryostatin (0.2 nM) and picolog (5 nM)
treatment lowered the AD-Index values for AD fibroblasts (for bryostatin: N=6, AD-Index
changes from 0.098±0.026 (SEM) to 0.025±0.03 (SEM); for picolog: N=4, AD-Index changes
from 0.065±0.022 (SEM) to -0.017±0.013 (SEM), respectively), indicating that these compounds
are efficacious at restoring a healthy phenotype of AD fibroblasts. The Aβ1-42-induction, and
bryostatin/picolog reversal of the AD-Biomarker phenotype suggest the AD-Biomarker‟s
potential in fibroblasts to monitor both disease progression and treatment response. Due to the
scarcity of bryostatin, synthetic analogs such as picolog represent novel potential for the
treatment of AD.
Disclosures: T.K. Khan, Full time, A. Employment (full or part-time); T.J. Nelson,
None; V.A. Verma, None; P.A. Wender, None; D.L. Alkon, None.
Poster
244. Abeta Toxicity I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 244.14/M7
Topic: C.01.c. Abeta toxicity
Title: Receptor-mediated binding and internalization of soluble amyloid beta polymers mediates
intracellular deposition of tau protein in 3T3 cells overexpressing 4-repeat human tau
Authors: S. LEONOV, S. SVENSSON, *K. SANDBERG;
Mol. Pharmacol., AstraZeneca R & D Sodertalje, Södertälje, Sweden