Multiple Targets for Alzheimer's Disease: γ–Secretase and Tau

Organizers: Donna Barten, Ph.D., Bristol-Myers Squibb; Barbara Petrack, Ph.D., Drew University; and Barbara Tate, Ph.D., Pfizer; Global Research & Development


This is an all day event.

Alzheimer's disease (AD) is characterized by the neuropathological lesions, plaques and tangles, largely composed of beta-amyloid (Ab) peptide and hyperphosphorylated tau, respectively. Because the enzymes that produce Ab and that phosphorylate tau are compelling targets for the treatment of AD, intense focus has yielded important understanding of some aspects of their biology. Proteolytic enzymes that process the amyloid precursor protein, notably gamma-secretase and BACE, and tau kinases such as glycogen synthase kinase (GSK) have been identified and characterized. However, much remains to be discovered, making it challenging to develop therapeutic agents that can inhibit or modulate the activity of these enzymes. We will discuss the current understanding of the protein assembly that makes up the gamma-secretase complex, the substrates and cleavage activity of the enzyme, and what is known of the regulation of its activity. Tau, which normally binds to and stabilizes microtubules, is regulated by phosphorylation. However, hyperphosphorylated tau can no longer bind to microtubules and tends to self-aggregate, forming the tangles in AD. It is unclear which residues and kinases are relevant in AD, although GSK, which is elevated in AD, has been implicated. In addition, both gain of toxicity and loss of function hypotheses can explain tau's role in disease. New information gained from use of transgenic models of AD and the relationship between Ab and tau will be discussed.

8:30 - 9:00 Registration Check-In

9:00 - 9:10 Welcome and Introduction

9:10 - 9:55 Mark Shearman, Ph.D., Merck Research Laboratories, Boston, MA, "Gamma-Secretase Complex: Inhibition and Modulation."

9:55 - 10:40 Thomas Lanz, Ph.D., Pfizer Global Research & Development, Groton, CT, "Complex Pharmacology of "Classical" Gamma-Secretase Inhibitors."

10:40 - 11:00 Refreshments

11:00 - 11:45 Michael S. Wolfe, Ph.D., Brigham & Women's Hospital, Boston, MA, "Biochemistry of Presenilin and Presenilin-like Proteases."

11:45 - 12:30 David Holtzman, M.D., Washington University, St. Louis, MO, "Amyloid-beta Metabolism and the Pathogenesis of AD."

12:30 - 2:00 Lunch Break

2:00 - 2:45 Frank M. LaFerla, Ph.D., Univ California, Irvine, "Understanding the Links Between Aβ and Tau Pathology."

2:45 - 3:30 Peter Davies, Ph.D., Albert Einstein College of Medicine, Bronx, NY, "What Changes in Tau are Important in Pathogenesis?"

3:30 - 3:50 Refreshments

3:50 - 4:35 Michael L. Hutton, Ph.D., Mayo Clinic Jacksonville, FL, "Tau as the Final Common Denominator for Multiple Neurodegenerative Diseases."

4:35 - 5:20 Leonard Petrucelli, Ph.D., Mayo Clinic Jacksonville, FL, "The Role of CHIP and Chaperones in Tau Pathology."