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P1‐055: Impaired induction of neuronal immediate‐early gene expression correlates with contextual memory deficits in APP transgenic mice
Author(s) -
Riddell D.R.,
Warwick H.K.,
Li Z.,
Saraf K.,
Zhong W.,
Schack D.,
Comery T.A.,
Aschmies S.,
Monaghan M.,
Braithwaite S.P.,
Pangalos M.N.,
Hirst W.D.,
Reinhart P.H.
Publication year - 2008
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.2008.05.641
Subject(s) - genetically modified mouse , amygdala , hippocampus , neuroscience , transgene , arc (geometry) , immediate early gene , amyloid precursor protein , gene expression , effector , biology , impaired memory , memory impairment , gene , psychology , alzheimer's disease , microbiology and biotechnology , disease , medicine , cognition , genetics , geometry , mathematics
Background: Transgenic mouse models with neuronal expression of human amyloid precursor protein (APP) develop a range of Alzheimer’s disease (AD)-like alterations, including deposition of A and age-dependent deficits in learning and memory. The most popular hypothesis proposes that soluble, oligomeric forms of A mediate the memory deficits observed in APP transgenic animals prior to the formation of plaques. However, very little is known about the underlying molecular mechanisms leading to A mediated memory dysfunction. Methods: It has been known for some time that normal memory processes are associated with altered gene expression. This makes unraveling the molecular basis of memory dysfunction in AD ideally suited to transcriptional profiling. To that end, we have begun to characterize the molecular changes underlying early memory impairments in the Tg2576 mouse model of AD by analyzing the gene changes associated with memory formation in the brains of both wild-type and cognitively impaired Tg2576 mice. Results: In wild-type mice the formation of a strong contextual fear-related memory was associated with a robust induction (2-4 fold) of known immediate early genes (IEGs): c-fos, Jun-b, Erg1 and Nurr77, as well as the effector gene, Arc/Arg3.1 in both the amygdala and hippocampus. A number of genes not previously associated with memory formation were also significantly upregulated. None of these genes were induced in the Tg2576 implying that A antagonizes memory formation upstream of IEG induction. Conclusions: These data, together with recent reports by others, suggest a scenario where soluble A species impair neuronal signaling in key mechanisms related to memory formation. Many of the genes identified to be differentially regulated are downstream of NMDA receptor signaling, indicating the importance of these pathways in A induced memory impairments. We are currently examining the effect of A -directed therapeutics on reversing the memory and IEG deficits in the Tg2576 mice.