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Series GSE36237 Query DataSets for GSE36237
Status Public on Mar 09, 2012
Title Tg2576 and wild-type mice treated with PDE9A-inhibitor
Organism Mus musculus
Experiment type Expression profiling by array
Summary Many forms of synaptic plasticity are critically dependent upon production of cGMP to trigger activity-dependent increases in synaptic size and strength. Phosphodiesterase 9A (PDE9A) is a high affinity, cGMP-specific phosphodiesterase with widespread distribution in the central nervous system. Inhibition of PDE9A results in significant accumulation of cGMP in brain tissue and cerebrospinal fluid (CSF) of rodents, and increases CSF cGMP in human volunteers. We hypothesized that chronic exposure to a PDE9A inhibitor, and the associated elevations in brain cGMP could provide a therapeutic benefit to vulnerable synapses chronically exposed to Aβ in transgenic mice over-expressing human mutant amyloid precursor protein (Tg2576 mice). A total of N=20 animals per group of 4 month old Tg2576 mice and non-transgenic littermates (WT) were implanted with Alzet osmotic minipumps to deliver vehicle or the PDE9A inhibitor PF-04447943. Neurobehavioral outcomes were measured as conditioned fear response after 28 days of treatment and subsequently brains were harvested for measurement of Aβ, gene expression profiling or synaptic density as assessed by Golgi staining of dendrites. Dendritic spine density on apical dendrites of CA1 neurons exhibited a small but significant deficit in the density of dendritic spines in vehicle treated Tg2576 mice as compared to WT mice. This deficit was ameliorated by 30 days of exposure to PF-04447943. No significant drug effect was observed in WT mice. No significant effects of drug treatment were observed on Aβ levels in Tg2576 mice. Behavioral analysis of Tg2576 mice showed deficits in fear conditioning as early as 2 months old, and therefore were considered unlikely to be due to the accumulation of oligomeric Aβ. These deficits were not affected by drug treatment. Transcriptional profiles of Tg2576 mice treated with drug compared to vehicle showed evidence of regulation of pathways related to synaptic plasticity and remodeling of the dendritic cytoskeleton, consistent with stabilization of vulnerable spine structure. These data supports the hypothesis that PDE9A inhibition can stabilize vulnerable synapses early in the Alzheimer’s disease process.
 
Overall design 4-month old Tg2576 mice and non-transgenic (WT) littermates were implanted with minipumps to deliver vehicle or the PDE9A-inhibitor, PF-04447943, for 28 days. At the end of the study, hippocampus and frontal cortex were dissected from n=8 mice per group, RNA was isolated, and hybridized to Affymetrix 430 2.0 mouse whole genome microarray.
 
Contributor(s) Lanz TA, Yates PD
Citation Kleiman, R.J., Lanz, T.A., Finley, J.E., Bove, S.E., Majchrzak, M.J., Becker, S.L., Carvajal-Gonzales, S., Kuhn, A.M., Wood, K.M., Mariga, A. and Nelson, F.R., 2010. Dendritic spine density deficits in the hippocampal CA1 region of young Tg2576 mice are ameliorated with the PDE9A inhibitor PF-04447943. Alzheimer's & Dementia, 6(4),pp.S563-S564 http://dx.doi.org/10.1016/j.jalz.2010.05.1922
Submission date Mar 02, 2012
Last update date Feb 11, 2019
Contact name Phillip Yates
E-mail pyatesgene@gmail.com
Organization name Pfizer Inc.
Street address 440 Eastern Point Rd
City Groton
State/province CT
ZIP/Postal code 06340
Country USA
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (64)
GSM884874 Hipp PDE9 Tg+, rep1
GSM884875 Hipp PDE9 Tg+, rep2
GSM884876 Hipp PDE9 Tg+, rep3
Relations
BioProject PRJNA153153

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Supplementary file Size Download File type/resource
GSE36237_RAW.tar 245.6 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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