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The b-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism

Petratos, S, Qiao-Xin, L, George, AJ, Hou, X, Unabia, SE, Hatzinisiriou, I, Maksel, D, Aguilar, MI and Small, DH 2008 , 'The b-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism' , Brain, vol. 131, no. Part 1 , pp. 90-108 , doi:

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Neuritic abnormalities are amajor hallmark of Alzheimer’s disease (AD) pathology. Accumulation of b-amyloid
protein (Ab) in the brain causes changes in neuritic processes in individuals with this disease. In this study, we
show that Ab decreases neurite outgrowth from SH-SY5Y human neuroblastoma cells. To explore molecular
pathways by which Ab alters neurite outgrowth, we examined the activation and localization of RhoA and
Rac1 which regulate the level and phosphorylation of the collapsin response mediator protein-2 (CRMP-2). Ab
increased the levels of the GTP-bound (active) form of RhoA in SH-SY5Ycells.This increase in GTP-RhoA correlatedwith
an increase in an alternatively spliced formof CRMP-2 (CRMP-2A) and its threonine phosphorylated
form. Both a constitutively active form of Rac1 (CA-Rac1) and the Rho kinase inhibitor,Y27632, decreased levels
of the CRMP-2A variant and decreased threonine phosphorylation caused by Ab stimulation. The amount of
tubulin bound to CRMP-2 was decreased in the presence of Ab but Y27632 increased the levels of tubulin
bound to CRMP-2. Increased levels of both RhoA and CRMP-2 were found in neurons surrounding amyloid plaques
in the cerebral cortex of the APP(Swe) Tg2576 mice.We found that there was an increase in threonine
phosphorylation of CRMP-2 inTg2576 mice and the increase correlated with a decrease in the ability of CRMP-
2 to bind tubulin.The results suggest that Ab-induced neurite outgrowth inhibition may be initiated through a
mechanism in which Ab causes an increase in Rho GTPase activity which, in turn, phosphorylates CRMP-2 to
interfere with tubulin assembly in neurites.

Item Type: Article
Authors/Creators:Petratos, S and Qiao-Xin, L and George, AJ and Hou, X and Unabia, SE and Hatzinisiriou, I and Maksel, D and Aguilar, MI and Small, DH
Journal or Publication Title: Brain
ISSN: 0006-8950
DOI / ID Number:
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The definitive version is available from Oxford University Press.

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