[Abstract Title]. - Society for Neuroscience

modulates neuronal function and synaptic plasticity. It enhances the induction of long-term
potentiation via its modulatory effects on NMDA receptor function and its ability to stimulate the
translation of dendritically expressed transcripts. Reelin binds to the very-low-density lipoprotein
receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). This induces their clustering and
tyrosine phophorylation of the adapter protein Dab1 that interacts with cytoplasmic NPxY motifs
of VLDLR, ApoER2, and amyloid precursor protein (APP). Reelin also affects the formation of
amyloid-β plaques and neurofibrillary tangles, the two neuropathological hallmarks of AD:
Reelin-induced receptor clustering is necessary for recruitment of fyn and src tyrosine kinases to
Dab1 and the recruitment and activation of kinases that are key mediators of Tau
phosphorylation. In addition, Reelin increases the intracellular interaction of Dab1 with both
ApoER2 and APP and promotes their cell surface localization and activation of nonamyloidogenic
APP processing in-vitro. Here, we tested the hypothesis that reduction in Reelin
expression and signaling are causally involved in neurodegenerative processes of late-onset AD
by favoring amyloidogenic processing of APP and amyloid-β plaque formation in-vivo. We
crossed Reelin heterozygous knockout mice with transgenic ArcAβ mice. We assessed the
cognitive status of the F1 wild-type, single- and double-transgenic mutant mice at 3, 6, and 9
months of age using an object-in-context recognition task. The amyloid-β plaque burden was
investigated in the hippocampus and cerebral cortex using immunohistochemistry and unbiased
stereological quantification. This was complemented by biochemical examinations of soluble
and insoluble fractions of brain homogenates using western blotting and ELISA focusing on
Aβ40/42 peptide productions. We found a precocious formation of amyloid-β plaques in Reelindeficient
ArcAβ double-transgenic mice compared to single-mutant AD mice, which was
associated with selective hippocampal-dependent memory impairment. Our results confirm a
critical role of Reelin-dependent signaling in APP processing and suggest that aging-related
decline in Reelin expression represent an important driving force of senile plaque formation and
cognitive decline associated with late-onset AD.
Disclosures: I. Knuesel , None; S. Kocherhans, None; F. Crestani, None; C. Sidler, None; J.
Fritschy, None.
Poster
243. Abeta Assembly and Deposition
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 243.9/K3
Topic: C.01.b. Abeta assembly and deposition
Support: Alzheimer's Association Research Grant
Title: Endogenous testosterone prevents amyloid deposition in transgenic animal brain