S4-02-04: From neuropsychology to neuroimaging in neurodegenerative diseases

Abstract

not available. S4-02-06 REGULATORY PERSPECTIVE OF MCI Karl Broich, Federal Institute of Drugs and Medical Devices, Bonn, Germany. Contact e-mail: k.broich@bfarm.de Abstract not available. WEDNESDAY, JULY 19, 2006 SYMPOSIA S4-03 DISEASE MECHANISMS (SIGNAL TRANSDUCTION)not available. WEDNESDAY, JULY 19, 2006 SYMPOSIA S4-03 DISEASE MECHANISMS (SIGNAL TRANSDUCTION) S4-03-01 EVIDENCE THAT ABERRANT POST-TGN TRAFFICKING OF ALZHEIMER’S APP IS SUFFICIENT TO ELEVATE BRAIN A-BETA 42 AND MAY UNDERLIE MUTANT PRESENILIN ACTION Sam Gandy, Yun-wu Zhang, Annat Ikin, Stephen Schmidt, Roxanne Sheffield, Ralph Nixon, Francesca-Fang Liao, Paul Matthews, Huaxi Xu, Michelle Ehrlich, Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia, PA, USA; Burnham Institute, La Jolla, CA, USA; Nathan Kline Institute, Orangeburg, NY, USA. Contact e-mail: samgandy@earthlink.net Mutations in presenilin 1 (PS1) cause familial Alzheimer’s disease (FAD) by increasing cerebral amyloidogenic A-beta peptide ratios, expressed as A-beta 42/40 42. We investigated A-beta speciation in mice expressing an A-beta precursor protein (APP):furin chimera highly concentrated in the neuronal trans-Golgi network (TGN). Brain A-beta 42/40 42 ratios from APP:furin mice were similar to reported ratios associated with FADmutant PS1, lending plausibility to the model that altered trafficking of APP out of the TGN could underlie PS1-linked FAD. The association of mutant PS1 with delayed TGN exit was confirmed using a cell-free assay based on APP transport vesicle biogenesis from TGN-rich fractions prepared from cerebrocortical neurons of PS1 M146V knock-in mice. In intact neurons, reduced cell-surface arrival of newly synthesized APP was associated with the presence of PS1 M146V. These data support the notion that selective localization of APP to the TGN is sufficient to elevate the A-beta 42/40 42 ratio, and that delayed exit of APP from the cerebrocortical neuronal TGN is a phenotype associated with the presence of mutant PS1. S4-03-02 ROLE OF P70 S6 KINASE IN ALZHEIMER’S DISEASE Jin Jing Pei, Wen-Lin An, Cecilia Bjorkdahl, Xu Li, Xinwen Zhou, Bengt Winblad, Karolinska Institutet, Huddinge, Sweden. Contact e-mail: Jin-Jing.Pei@neurotec.ki.se The cytoplasmic isoform of ribosomal S6 kinase 1 (RSK1), the 70-kDa S6 kinase (p70S6K), is a Ser/Thr (S/T) -directed kinase that regulates the phosphorylation of the 40S ribosomal protein S6. Phosphorylation and activation of p70S6K have been suggested to be mediated by both phosphoinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Our previous studies indicated that both PI3K and MAPK pathways are aberrantly regulated in Alzheimer’s disease (AD) brains. In the study, we wanted to investigate the role of p70S6K in AD pathogenesis. In a series of studies, we found: 1) an increased immunoreactivity of the phosphorylated (p) / activated form of p70S6K, and its upstream kinase: mammalian target of rapamycin, in AD as compared with control brains; 2) a colocalization of p-p70S6K with PHF-tau in neurons bearing neurofibrillary tangles (NFTs) and pre-tangles; 3) that p70S6K activation and tau hyperphosphorylation can be induced by a selective protein phosphatase (PP) -2A inhibition in rat brain slices, as well as 100 M zinc in SH-SY5Y cells and primary cultured neurons; 4) that phosphorylation and activation of p70S6K are preferentially regulated by the PI3K pathway, together with the MAPK pathway; 5) that p70S6K can mediate tau phosphorylation and synthesis; and 6) that p70S6K activation does not increase phosphorylation of neurofilament. These suggested p70S6K might play a significant role in tau abnormalities such as hyperphosphorylation, accumulation, assembly into paired helical filaments and neurofibrillary tangle formation, accompanied by microtubule disruption. Activation of p70S6K in AD might be caused by either upregulated PI3K and MAPK pathways, or downregulated PP-2A. S71 Symposia S4-03: Disease Mechanisms (Signal Transduction)