NeuroMolecular Medicine

, Volume 2, Issue 2, pp 89–99 | Cite as

Fast axonal transport misregulation and Alzheimer’s Disease

  • Gerardo Morfini
  • Gustavo Pigino
  • Uwe Beffert
  • Jorge Busciglio
  • Scott T. Brady
Article

Abstract

Pathological alterations in the microtubule-associated protein (MAP) tau are well-established in a number of neurodegenerative disorders, including Alzheimer’s Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit abnormal phosphorylation on specific serine and threonine residues in these diseases. A large body of biochemical, genetic, and cell biological evidence implicate two major serine-threonine protein kinases, glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for both normal and pathological phosphorylation of tau protein in vivo. What remains unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT) formation are causal or secondary to initiation of neuronal pathology. In fact, many studies have indicated that tau misphosphorylation is not the causal event. Interestingly, some of these kinase and phosphatase activities have recently merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and GSK-3 have been recently shown to regulate kinesin-driven motility. Given the essential role of FAT in neuronal function, an alternate model for pathogenesis can be proposed. In this model, misregulation of FAT induced by an imbalance in specific kinase-phosphatase activities within neurons represents an early and critical step for the initiation of neuronal pathology. Such a model may explain many of the unique characteristics of late onset of neurological diseases such as AD.

Index Entries

Kinesin fast axonal transport CDK5 GSK-3 glycogen synthase kinase 3 Alzheimer’s disease presenilins 

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Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Gerardo Morfini
    • 3
  • Gustavo Pigino
    • 2
  • Uwe Beffert
    • 1
  • Jorge Busciglio
    • 2
  • Scott T. Brady
    • 3
  1. 1.Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallas
  2. 2.Department of NeuroscienceUniversity of Connecticut Health CenterFarmington
  3. 3.Dept. of Cell BiologyUniversity of Texas Southwestern Medical Ctr.Dallas

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