Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1.
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.
Lazarov
Orly
O
Department of Anatomy and Cell Biology, The University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Morfini
Gerardo A
GA
Pigino
Gustavo
G
Gadadhar
Archana
A
Chen
Xiangjun
X
Robinson
John
J
Ho
Hanson
H
Brady
Scott T
ST
Sisodia
Sangram S
SS
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013118:Spinal Cord Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
D053764:Presenilin-1