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The Journal of Neuroscience, June 15, 2003, 23(12):5219-5226

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Selectively Reduced Expression of Synaptic Plasticity-Related Genes in Amyloid Precursor Protein + Presenilin-1 Transgenic Mice

Chad A. Dickey,^1 * Jeanne F. Loring,^2 * Julia Montgomery,² Marcia N. Gordon,¹ P. Scott Eastman,² and Dave Morgan¹

¹Alzheimer's Disease Research Laboratory, Department of Pharmacology, University of South Florida, College of Medicine, Tampa, Florida 33612, and ²Department of Life Sciences, Incyte Genomics, Palo Alto, California 94304

A critical question in Alzheimer's disease (AD) research is the cause of memory loss that leads to dementia. The amyloid precursor protein + presenilin-1 (APP+PS1) transgenic mouse is a model for amyloid deposition, and like AD, the mice develop memory deficits as amyloid deposits accumulate. We profiled gene expression in these transgenic mice by microarray and quantitative RT-PCR (qRT-PCR). At the age when these animals developed cognitive dysfunction, they had reduced mRNA expression of several genes essential for long-term potentiation and memory formation (Arc, Zif268, NR2B, GluR1, Homer-1a, Nur77/TR3). These changes appeared to be related to amyloid deposition, because mRNA expression was unchanged in the regions that did not accumulate amyloid. Transgene expression was similar in both amyloid-containing and amyloid-free regions of the brain. Interestingly, these changes occurred without apparent changes in synaptic structure, because a number of presynaptic marker mRNAs (growth-associated protein-43, synapsin, synaptophysin, synaptopodin, synaptotagmin, syntaxin) remained stable. Additionally, a number of genes related to inflammation were elevated in transgenic mice, primarily in the regions containing amyloid. In AD cortical tissue, the same memory-associated genes were downregulated. However, all synaptic and neuronal transcripts were reduced, implying that the loss of neurons and synapses contributed to these changes. We conclude that reduced expression of selected genes associated with memory consolidation are linked to memory loss in both circumstances. This suggests that the memory loss in APP+PS1 transgenic mice may model the early memory dysfunction in AD before the degeneration of synapses and neurons.

Key words: Alzheimer's; amyloid; immediate early genes; IEGs; memory; transgenic; real time PCR; cDNA microarray

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Received Dec. 3, 2002; revised Apr. 4, 2003; accepted Apr. 7, 2003.

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