Journal of Alzheimer’s Disease 6 (2004) 537–545 537 IOS Press Discussion Axonal transport hypothesis moves on to implicate presenilin 1 : Alzheimer research forum live discussion Jorge Busciglio and Scott Brady led this live discussion, an update of last year’s initial Live Discussion of axonal transport as an underlying factor in neurodegeneration. http://www.al2forum.org/nes/for/jounal/busciglio/default.asp Participants: Akihiko Takashima, (Institute of Physical and Chemical Sciences (RIKEN), Japan); Peter Klein, (University of Pennsylvania); Leo Kim, (University of Pennsylvania); Frank LaFerla, (University of California, Irvine); Changiz Geula, (Beth Israel Deaconess Medical Center, Boston Massachusetts); Jorge Busciglio, (University of California, Irvine); Scott Brady, (University of Illinois at Chicago College of Medicine); Martha Stokely, (University of Florida Gainesville); Nikolaos Tezapsidis, (Columbia University); Gunnar Gouras, (Cornell University); Gabrielle Strobel, (Alzheimer Research Forum); Keith Crutcher, (University of Cincinnati, Ohio); Diego Forero, (National University of Colombia, Bogota). Background text by Jorge Busciglio and Scott Brady Neuronal cells are highly sensitive to transport de- fects because of their highly polarized morphology and large number of specialized microdomains. For their survival and proper function, neurons depend on the ef- ficient delivery of proteins from the cell body to neuritic processes. Axons in particular are highly susceptible to transport deficiencies because they lack the elements necessary for protein synthesis. In this context, we have suggested that defects in protein transport play a criti- cal role in Alzheimer’s disease (AD) and other? neu- rodegenerative conditions [1]. Experimental evidence indicates that kinase and phosphatase activities are key regulators of fast axonal transport. Two major serine- threonine protein kinases, glycogen synthase kinase- 3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), have been implicated as major kinases responsible for both normal and pathological phosphorylation of tau 1 Note: The transcript has been edited for clarity and accuracy. protein in AD. Moreover, GSK-3β, which is highly homologous to GSK-3β, has been recently implicated in the modulation of Aβ production [2]. Both CDK5 and GSK-3β have also been shown to regulate kinesin- driven motility. Specifically, GSK-3β phosphorylates kinesin light chains in vivo and causes the release of kinesin from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I-driven motility [3]. Given the essential role of axonal transport in neu- ronal function, a misregulation of transport induced by an imbalance in specific kinase/phosphatase activities within neurons may represent an early and critical step of neuronal pathology. Presenilin Mutations: They Do More Than Increase Aβ Significant evidence indicates that presenilin-1 (PS1) is essential for gamma-secretase activity. At the same time, there is also considerable evidence to suggest that PS1 has additional physiological functions, includ- ing control of calcium homeostasis, cell-cycle regu- lation, neurite outgrowth, apoptosis, membrane traf- ISSN 1387-2877/04/$17.00  2004 – IOS Press and the authors. All rights reserved