Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1.

Abstract

Presenilins (PS) play a central role in gamma-secretase-mediated processing of beta-amyloid precursor protein (APP) and numerous type I transmembrane proteins. Expression of mutant PS1 variants causes familial forms of Alzheimer's disease (FAD). In cultured mammalian cells that express FAD-linked PS1 variants, the intracellular trafficking of several type 1 membrane proteins is altered. We now report that the anterograde fast axonal transport (FAT) of APP and Trk receptors is impaired in the sciatic nerves of transgenic mice expressing two independent FAD-linked PS1 variants. Furthermore, FAD-linked PS1 mice exhibit a significant increase in phosphorylation of the cytoskeletal proteins tau and neurofilaments in the spinal cord. Reductions in FAT and phosphorylation abnormalities correlated with motor neuron functional deficits. Together, our data suggests that defects in anterograde FAT may underlie FAD-linked PS1-mediated neurodegeneration through a mechanism involving impairments in neurotrophin signaling and synaptic dysfunction.

• Authors: Orly Lazarov, Gerardo A Morfini, Gustavo Pigino, Archana Gadadhar, Xiangjun Chen, John Robinson, Hanson Ho, Scott T Brady, Sangram S Sisodia
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 27 Issue 26 Pg. 7011-20 (Jun 27 2007) ISSN: 1529-2401 [Electronic] United States
• PMID: 17596450 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Presenilin-1

Topics

• Alzheimer Disease (genetics, metabolism)
• Animals
• Axonal Transport (physiology)
• Genetic Predisposition to Disease (genetics)
• Humans
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Transgenic
• Motor Neuron Disease (genetics, metabolism, physiopathology)
• Motor Neurons (metabolism, pathology)
• Mutation (genetics)
• Nerve Degeneration (genetics, metabolism, physiopathology)
• Peripheral Nervous System Diseases (genetics, metabolism, physiopathology)
• Presenilin-1 (genetics, metabolism)
• Sciatic Neuropathy (genetics, metabolism, physiopathology)
• Spinal Cord Diseases (genetics, metabolism, physiopathology)