Keystone Symposia Meeting, Part 1—Alzheimer’s Disease: Genes, Cellular Pathways and Therapies

Series - Keystone Symposium: Alzheimer's Disease 2006:

By Minji Kim, Alice Lu, and Rudy Tanzi.

See PDF of the full series of meeting summaries.

This Keystone Symposia meeting on Alzheimer disease, organized by Rudy Tanzi, Massachusetts General Hospital, Boston, and Virginia Lee, University of Pennsylvania, Philadelphia, at Beaver Run Resort, Breckenridge, Colorado, focused on the molecular underpinnings of Alzheimer disease (AD) and frontal temporal dementia (FTD), covering genetic risk factors, cellular pathways, and emerging therapies. The program was enhanced by running parallel with another Keystone Symposia meeting organized by Jeff Kelly, The Scripps Research Institute, La Jolla, California, and Susan Lindquist, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, on the role of abnormal protein folding in disease.

Over the past two decades, studies of AD at the genetic, molecular, and cell biological level have revealed a host of genes, proteins, and biological pathways that impact the pathogenesis of this disease. Characterization of these pathogenic pathways has suggested several promising therapeutic strategies for treating and preventing AD, based on curbing the accumulation of the Aβ peptide in brain, regulating tau hyperphosphorylation, modulating inflammatory responses, and enhancing neurotransmitter function. This meeting covered the newest findings regarding the genetics of AD, Aβ generation and clearance pathways, regulation of tau, relevant animal models, novel therapeutic strategies, and advances in imaging and biomarkers for AD diagnosis. Overall, it was a very exciting meeting, especially since all of the speakers mainly presented new and unpublished findings. In many ways, this meeting granted a sneak peek into what will be presented at this year's international AD meetings in Geneva and Madrid, and from many of the top researchers in the field. We also had the "three S" formula that makes for a great Keystone meeting: Great Science, Bright Sun, and Incredible Snow. The meeting was very well attended with a capacity ~300 at the AD meeting alone. As the Keystone staff put it, there was clearly a great "buzz" at this meeting with a feeling of great movement and progress in the air. Many of the participants also commented that this was the best AD meeting they have attended in several years.

Keynote Session: Sangram S. Sisodia and Cynthia Kenyon
Sangram Sisodia, University of Chicago, Illinois, focused on the molecular neurobiology of Alzheimer disease, including an overview of APP processing pathways and the roles of BACE (β-secretase) and of the presenilins (as part of the γ-secretase complex). He described the effects of PS1 mutations, including impaired transport of APP, kinesin, and Trk receptors in axons; inhibition of enrichment-mediated proliferation and survival of progenitor cells in the dentate gyrus; and promotion of vulnerability of cortical neurons to lesions. He also reviewed data from his recent paper in Cell showing in vivo evidence that exercise attenuates AD pathology in transgenic mice (see ARF related news story). Mice housed under conditions of environmental enrichment, including robust running wheel activity, exhibited decreased levels of brain Aβ—potentially via up-regulation of neprilysin (an Aβ degradation enzyme)—and also transthyretin (TTR) in hippocampus. Following up on these data, Sisodia showed that genetic reduction of TTR accelerated Aβ deposition in transgenic mice (TTR +/-). Based on his data, Sisodia argued that simple physical exercise can be an effective preventive measure against AD.

Cynthia Kenyon, University of California, San Francisco, illustrated the importance of controlling aging by altering genes involved in the aging process. She described the role of C. elegans DAF-2, which encodes a hormone receptor similar to the human insulin and IGF-1 receptors. Mutations that reduced the activity of DAF-2 doubled the lifespan of the roundworms. Longevity of DAF-2 mutants required DAF-16, the normal function of which is to extend lifespan. As DAF-2 is turned down and DAF-16 is turned up, FOXO transcriptional activity is increased. Together, DAF-2 and DAF-16 control a battery of downstream genes whose functions affect lifespan. In addition, Kenyon reported that heat shock factor-1 (HSF-1) has to be present in order for DAF-2 mutants to live long, suggesting a role for heat shock and stress-induced proteins. Many of the genes affected by DAF-2/DAF-16 are regulated by FOXO transcription factor, and included various antioxidant, chaperone, anti-microbial, and metabolic genes. Kenyon also demonstrated that the lifespan of C. elegans was influenced by its perception of soluble and volatile substances in the environment. Finally, a nematode that reached the very ripe age of 142 days was revealed; however, no details regarding its genetic makeup and growth conditions were presented.

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  1. Sorrento: More Fun, Less Amyloid for Transgenic Mice

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