[Abstract Title]. - Society for Neuroscience

expressed in the hippocampal formation, we completed a second study examining both
hippocampal and cerebellar extracts in older retromer-deficient mice. Results suggest an
interesting interaction, such that retromer-deficient mice have increases in tau phosphorylation in
the hippocampus versus the cerebellum, compared to the between-region difference observed in
wildtype mice. To confirm, extend and clarify these observations we are currently A) replicating
this analysis in a larger number of subjects; B) relying on brain slice histology to identify which,
if any, hippocampal subregion has the greatest effect; and, C) testing for tau
hyperphosphorylation in retromer-deficient mice expressing human amyloid precursor protein.
Disclosures: A.S. Bender, None; E. Planel, None; S.A. Small , None; K. Duff, None.
Poster
245. Tau and Alzheimer's disease
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 245.11/O5
Topic: C.01.h. Tau
Title: The novel calpain-inhibitor A-705253 prevents stress-induced tau hyperphosphorylation
in vitro and in vivo
Authors: *R. BITNER 1 , A. L. NIKKEL 1 , S. MARKOSYAN 1 , M. W. DECKER 1 , A. HAHN 2 , J.
SCHOEMAKER 2 , A. MOELLER 2 ;
1 Abbott Labs., Abbott Park, IL; 2 Abbott Labs., Ludwigshafen, Germany
Abstract: Calpains are a family of calcium-dependent cysteine proteases expressed by numerous
cell types that participate in signal transduction, cytoskeletal architecture and apoptosis. In
neuronal cells, calcium-mediated overactivation of calpain has been implicated in several
neurodegenerative disorders, including Alzheimer‟s disease (AD). Hyperphosphorylation of the
microtubule-associated protein tau and the subsequent aggregation of tau filaments resulting in
the formation of neurofibrillary tangles are recognized etiological pathways in AD pathology.
Cyclin-dependent kinase 5 (cdk5) is a major kinase responsible for tau hyperphosphorylation in
AD that in part may involve calpain-mediated conversion of a cdk-5 regulatory activating protein
(p35 to p25). In the present study, we examined the effects of calpain inhibition both in vitro and
in vivo on tau phosphorylation. In hippocampal slices, lowering medium temperature to 33°C
increased tau phosphorylation at the AT8 site as measured by Western blot analysis. Incubation
with the novel small molecule calpain inhibitor A-705253 blocked the 33°C-induced tau
phosphorylation with an IC50 of 100 nM. In vivo, pentobarbital-induced hypothermia or acute
systemic LPS treatment increased tau phosphorylation in Mossy Fibers of the CA3 hippocampus
of non-transgenic mice, as measured immunohistochemically at the AT8 site. A-705253 (3-10