Poster Session P3: Related Neurodegenerative Conditions - Frontotemporal Dementias, FTDP-17 $449

28 days. Semi-quantitative analysis of the volume of the hippocampus mad in situ terminal transferase-mediated dUTP nick end labeling (TUNEL) staining were performed. Isolated brain microvascular endothelial cells (EC) were treated with galantamine to determine its capacity to induce HO-1 in vitro. Results: Systolic blood pressure was significantly increased in 3-month-old SHR in comparison with age-matched WKY regardless of CO treatment. A decrease of the hippocampal volume was already taken place in 3-month-old SHR compared to WKY, and exacerbated at 4-month-old. In CO treated SHR, the progression of volume reduction was inhibited ~86% versus SHR. In situ TUNEL staining showed only a few TUNEL-positive EC nuclei in the hippocampus of WKY, whereas some positive EC were detected in SHR. CO treatment apparently decreased TUNEL positive EC number in the hippocampus. In vitro, cerebrovascular EC treated with CO showed to decrease JNK activation and apoptosis induced by H202 treatment. Galantamine treatment induced HO-1 in EC, and prevented H202-induced JNK activation and apoptosis.

1 2 3 4

HO-1

1: control WKY rats EC 2: SHR EC 3: SHR EC + GL I /~M 4: SHR EC + GL 10/z M

Conclusions: CO prevented H202-induced EC death providing one mech- anism by which CO can elicit vasoprotection. Demonstrated here is that CO provides protective effects against hypertension related vascular injury in the VD model by preventing apoptosis of EC. Galantamine was shown to have a property to induce HO-1 in EC and this might be a possible mechanism of its vasoprotective effects in vascular related dementia.

• ~/-SECRETASE PROCESSING OF VE-CADHERIN R E G U L A T E S CBP-MEDIATED T R A N S C R I P T I O N

Geo Serban*, Philippe Mararnband, Claudia Litterst, Nikolaos Robakis. Mount Sinai School of Mud, New York, NY, USA. Contact e-mail: geo.serban @ mssm.edu

Background: Presenilin-1 (PSi), a multipass transmembrane protein in- volved in familial forms of Alzheimer's disease, is a critical cofactor for the y-secretase protease. Results from our laboratory have recently revealed a novel signal transduction pathway where the PS l/y-secretase system cleaves the cell adhesion protein neural (N)-cadherin to regulate CBP-mediated tran- scription. Indeed, N-Cad/CTF2, the y-secretase,derived cytoplamic fragment of N-cadherin binds to the transcriptional coactivator CBP, sequesters it into the cytoplasm and ultimately represses its transcriptional activity. The cAMP/PKA signaling pathway regulates both CBP transcriptional activity and endothelial cell permeability. Methods and Results: Here we show that vascular endothelial (VE)-cadherin, an endothelial specific cadherin homologue, is cleaved by the PS1/y-secretase system in primary endothe- lial HUVEC cells. By coimmunoprecipitation experiments we found that VE-cadherin interacts with PS 1 and that PS 1 residues 330 to 360 (PS 1 A330- 360) are necessary for this interaction. Furthermore, retroviral expression of the PS1 mutant PS1A330-360 in HUVEC cells prevented both PS1/VE- cadherin interaction and VE-cadherin cleavage by y-secretase, while PS1 endoproteolysis is not affected. Furthermore, our data show that similar to N-cadherin, the y-secretase-derived cytoplasmic fragment of VE-cadherin binds to CBP and represses PKA-stimulated CBP-dependent transactivation. Conclusions: These data indicate that: (i) The PS1/VE-cadherin interaction is critical for the y-secretase cleavage of VE-cadherin. (ii) PS1 endoprote-

olysis and ¥-secretase cleavage of VE-Cadherin may involve independent activities, and (iii) the cytoplasmic domain of VE-cadherin (VE-Cad/CTF2) is able to inhibit PKA-stimulated CBP-dependent transactivation suggesting a possible link between y-secretase cleavage of VE-cadherin and cAMP- mediated signal transduction, a process linked to cellular permeability regulation in endothelial cells. Supported by NIH, AGO8200

~ A B S T R A C T W I T H D R A W N

Poster Session P3: Related Neurodegenerat ive Condit ions - Fronto tempora l Dement ias , FTDP-17

• FAMILIAL F R O N T O T E M P O R A L D E M E N T I A ASSOCIATED W I T H T H E NOVEL TAU MUTATION T427M

Giorgio Giaccone .1 , Giacomina Rossi 1, Giuseppe Di Fede l, Gabriella Marcon 1, Laura Farina 1, Leonardo Sacco 2, Fabrizio Tagliavinil. ] Istituto Nazionale Neurologico Carlo Besta, Milano, Italy," 2 Clinica Neurologica 3, Ospedale San Paolo, Milano, Italy. Contact e-mail: giaccone @ istituto-besta, it

Background: Several pathogenic mutations of the tau gene have been identified in families with neurodegenerative disorders. The clinical phe- notype is characterised by behavioral, cognitive and motor disturbances. Objective: Aim of this study was to elucidate the characteristics of the disease associated with the novel tan mutation T427M. Methods: We investigated the tan gene in an Italian kindred with familial dementia and carried out a clinical, neuropsychological and neuroradiological study in the proband. So far, no neuropathological data are available. Results: At age 60, the proband developed language disturbances, personality changes and inappropriate social and eating behavior. At age 64, neuropsychological examination showed that language dysfunction was severe, but memory and orientation were relatively preserved. Two years later the patient was apathetic and mute. MRI showed asymmetrical fronto-temporal atrophy more severe on the left side and diffuse abnormal signal intensity of the fronto-temporai white matter that was reduced in extension. Asymmetrical atrophy of the heads of the candate nuclei was present, while the right mesial temporal lobe was relatively spared. The father of the prohand died at age 80 after a 8-year history of dementia. The paternal grandfather and a paternal uncle were reported demented. In the prohand, sequencing of the tau gene revealed a C to T transition at the second position of codon 427, resulting in theonine to metionine substitution. This mutation was absent in