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P2‐219: ADF/cofilin‐actin rods and synaptic loss in Alzheimer's disease
Author(s) -
Bamburg James R.,
Bernstein Barbara W.,
Davis Richard C.,
Goldsbury Claire,
Maloney Michael T.,
Marsden Ian T.,
Minamide Laurie S.,
Pak Chi W.,
Perry George,
Podlisny Marcia B.,
Selkoe Dennis J.,
Shaw Alisa E.,
Siedlak Sandra L.,
Whiteman Ineka T.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1268
Subject(s) - cofilin , microbiology and biotechnology , actin remodeling of neurons , hippocampal formation , actin , cytochalasin d , actin remodeling , biophysics , sarcomere , chemistry , dendritic spine , biology , actin cytoskeleton , cytoskeleton , biochemistry , neuroscience , myocyte , cell
Background: Glutathione S-transferase (GST) omega-1 (Gsto1) has a protection role against oxidative stress, a risk factor for Alzheimer disease (AD), vascular dementia and stroke. Previous studies identified a locus in human chromosome 10 that potentially modulates the age-at-onset (AAO) in Alzheimer’s disease. A SNP in Gsto1 a candidate gene located in this region was shown to affect the AAO. Methods: We combined gene expression profiling in mouse hippocampus with linkage analysis to characterize mechanisms of the regulation in gene expression and potential downstream targets of Gsto1. Results: In situ hybridization of the mouse brain revealed intense expression of Gsto1 in the hippocampus, primarily in CA2 and the CA3/CA2 border region. We uncovered an important variation in expression of Gsto1 in hippocampus, striatum and cerebellum of the BXD strains. The source of this variation is a cis-eQTL (LOD1⁄4 18.9 in hippocampus) with the C57BL/6J allele highly expressed in all brain tissues. We validated the Gsto1 cis-eQTL using allelic-specific expression analysis and identified 104 transcripts relatively highly correlated with the variation in expression of Gsto1 (r>0.50; P < 0.001). We analyzed if the expression of these genes could be modulated by Gsto1, and found 18 genes that have a trans-eQTL that coincide with the position of the Gsto1.Some of the transcripts moderately correlated with Gsto1 have been reported to be associated with AD, such as Eif4e (r 1⁄4 0.47, P < 0.001) and Tnfaip1 (r 1⁄4 0.40, p < 0.001). We constructed a genetic network for Gsto1 and the group of genes highly correlated with Gsto1 and with a potential role in AD, in order to dissect molecular architecture of AD. We analyzed if variation in expression of Gsto1 correlates with any behavioral tests that assess cognitive variation among mouse strains since a loss in cognitive function is the most predominant effect in AD patients. The expression of Gost1 is moderately correlated with fear conditioning response during third tone-shock pairing (r1⁄4 -0.42, p < 0.01), and the latency to enter an open quadrant in the zero maze (r 1⁄4 -0.33, p < 0.05). Conclusions: Our study supports the involvement of Gsto1 in AD and suggests the possibility that this involvement is not limited exclusively to AAO.