[Abstract Title]. - Society for Neuroscience

3 Dept Psychiat & Pharmacol, Vanderbilt Univ. Sch. Med., Nashville, TN; 4 Dept. of Cancer Biol.,
Vanderbilt Univ. and VA Med. Ctr., Nashville, TN
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by senile
plaque pathology, neurofibrillary tangles, and neuronal death, which result in impairment of
memory and cognitive function. AD is characterized by the progressive loss of the neurons in
specific brain regions. Chemokines are expressed not only in neuroinflammatory conditions, but
also constitutively by different cell types, including neurons in the normal brain, suggesting that
they may act as modulators of neuronal functions. It has been shown that MIP2, a mouse
chemokine ligand for the chemokine receptor, CXCR2, prevents Aβ induced apoptosis in
hippocampal neurons in vitro (Watson, K. et al. 2005). Based on these initial findings,
chemokines in the CNS appear to be neuroprotective, in contrast to the neurotoxic effects of
inflammatory cytokines. Our results indicate that pre-incubation of mixed primary neuronal
cultures with SB225002, an antagonist specific for CXCR2, blocked the MIP-2 rescue of
neurons from Aβ-induced apoptosis, indicating that the neuroprotective pathway functions
through CXCR2. Also, N-methyl D-aspartate (NMDA), a ligand for glutamate receptors,
attenuated CXCR2-mediated neuroprotection through persistent CXCR2 phosphorylation and
blockade of receptor. Based upon our morphological study, pretreatment with the NMDA
receptor antagonist memantine resulted in significant protection in vitro and in vivo against Aβ
effects on spine density and total dendritic length. Quantitative morphometric analysis of
pyramidal neurons from Aβ treated CXCR2 (-/-) neurons also showed protection by memantine
as assessed in vitro by drebrin staining, and in vivo by Golgi impregnated, stained neurons.
Pretreatment with SDF-1 (0.25µg/µl), ligand for the chemokine receptor CXCR4, showed only
partial protection against Aβ induced neurotoxicity in vivo and in vitro in contrast to strong
protection by MIP-2. Our results demonstrate that CXCR2 and CXCR4 offer neuronal protection
from the toxic effects of Aβ in vivo and in vitro.
Disclosures: S. Zaja-Milatovic, None; D. Raman, None; A.Y. Deutch , None; D. Milatovic,
None; G. Fan, None; A. Richmond, None.
Poster
244. Abeta Toxicity I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 244.3/L8
Topic: C.01.c. Abeta toxicity
Title: Development of new High Content fluorescence based Assay of soluble amyloid beta
polymer mediated cellular effects