On June 24, Don Price provided an extensive review on transgenic animal models and their value for the development of specific therapies for AD. Price presented recent data indicating that APH-1 is a component of the presenilin (PS) complex and that APH-1 is enriched in brain tissue and may participate in the trafficking of the PS complex to the cell surface. (See related news item) The development of specific inhibitors for Bace-1, nicastrin and APH-1 activity is emerging as a promising therapeutic strategy for Alzheimer's disease.

On June 25, Virginia Lee addressed the role of α-synuclein, which forms intracellular inclusions called Lewy bodies that can be found in Parkinson's disease, dementia with Lewy bodies (LB), and the LB variant of AD. LBs are also found in 50% of familial AD, sporadic AD and Down's syndrome brains. There are interesting similarities between α-synuclein and tau: both are present in multiple neurodegenerative diseases, localize to dystrophic neurites, are hyperphosphorylated, convert to insoluble forms and are present in diseases with and without Aß accumulation. Results of studies on transgenic mice expressing α-synuclein mutation A53T were presented. (See related news item. These animals exhibit severe neuropathology and motor impairment which suggest a central role for α-synuclein pathology in neurodegenerative diseases.

On June 26, Huda Zoghbi presented an overview of the role of polyglutamine expansions in neurodegeneration. Several oral sessions during the meeting were devoted to AD research. L. Hersh and M. Kindy chaired a colloquium on Aβ degradation and clearance.in AD. The participants addressed the role of neprilysin (L. Hersh), thiol oligopeptidase 1 (THOP1)(C. Abraham), endothelin converting enzyme (C. Eckman) and plasmin (S. Estus) on Aβ clearance and degradation. Based on the exciting results presented by these researchers, the emerging view is that activation of Aβ clearance by different enzymatic systems may be a viable therapeutic strategy for AD.

Giulio Pasinetti chaired a workshop on gene expression profiling of AD. Pasinetti presented novel results describing the use of surface-enhanced laser desorption ionization (SELDI) for the rapid protein profiling and identification of biomarkers present at different stages of AD including mild cognitive impairment (MCI), a clinical term used to describe memory decline or other aging-related cognitive impairments in individuals who do not yet have AD. J.M. Lee presented data on a regional gene expression profile analysis in AD brain and V. Haroutunian addressed the confirmation of brain microarray results using RT-PCR and functional studies. The results presented emphasized the importance of bioinformatic techniques to map disease stage- and region-specific gene expression patterns in AD that can be confirmed and extended for individual proteins by functional studies.

A session devoted to the hormonal control of cerebral amyloidogenesis in AD featured very interesting talks on the regulation of APP metabolism and Aβ generation by inter- and intracellular signals affecting protein phosphorylation and calcium influx (J. Buxbaum); the control of Aβ generation in the trans-Golgi network by estrogen (H. Xu); the increased susceptibility of female APP-transgenic mice to Aβ deposition (L.C. Walker); and the reduction of Aβ levels and deposition by estrogen in APP transgenic mice (M.S. Kindy). The results presented highlighted the critical role of estrogen in Aβ generation and deposition, probably by regulating APP trafficking within the late secretory pathway.

In a symposium devoted to presenilin biology, Todd Golde presented new data on the characterization of a novel family of presenilin homologs (PSH) with putative protease activity (see related news item), the role of cholesterol in the regulation of gamma-secretase activity and the characterization of a novel mutation in PS1 that reduces Aβ and Notch cleavage (see related news item ). In the same session, presentations by M. Fortini and A. Tandon clearly defined the importance of nicastrin for the stabilization of PS1 and for gamma-secretase activity and J. Busciglio (correspondent) presented new data on the regulation of kinesin-based axonal transport by PS1 and its de-regulation by PS1 mutations.

In summary, this was a successful meeting with valuable scientific contributions that allowed the interaction, exchange of ideas and the initiation of new collaborations between a good number of scientists working in AD and related disorders.-Contributed by Jorge Busciglio (symposium organizer)