P1-055: Impaired induction of neuronal immediate-early gene expression correlates with contextual memory deficits in APP transgenic mice

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Poster Presentations P1

ciated with prominent motoric impairment in these mice. Conclusions: Transgenic mice are described in which tau pathology develops to different extents comparable with the early and late stages of AD neurofibrillary pathology. These mice present with cognitive and motor deficits, respectively. P1-055

IMPAIRED INDUCTION OF NEURONAL IMMEDIATE-EARLY GENE EXPRESSION CORRELATES WITH CONTEXTUAL MEMORY DEFICITS IN APP TRANSGENIC MICE

D. R. Riddell1, H. K. Warwick1, Z. Li1, K. Saraf2, W. Zhong2, D. von Schack2, T. A. Comery1, S. Aschmies1, M. Monaghan1, S. P. Braithwaite1, M. N. Pangalos1, W. D. Hirst1, P. H. Reinhart1, 1 Wyeth Research, Princeton, NJ, USA; 2Wyeth Research, Cambridge, MA, USA. Contact e-mail: [email protected] 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. P1-056

AN ANALYSIS OF COMPONENTS OF THE EGFR/ MAP KINASE PATHWAY IN THE REGULATION OF APP PROCESSING

Daniel R. Marenda1, Aleister J. Saunders2, 1University of the Sciences in Philadelphia, Philadelphia, PA, USA; 2Drexel University, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: A central process in the pathogenesis of Alzheimer’s Disease (AD) is the generation and deposition of the Amyloid ␤ (A␤) peptide in AD patient brains. A␤ is a major component of amyloid plaques, and is generated through the intra-membrane proteolysis of the Amyloid Precursor Protein (APP). One of the proteases essential to the generation of A␤ is ␥-secretase. Thus, a deeper understanding of the endogenous factors that regulate ␥-secretase activity, and of how those factors specifically control ␥-secretase function, will likely be significant to our understanding of the mechanisms that contribute to AD pathogenesis. It has been previously reported that the MAP Kinase pathway is a key negative regulator of ␥-secretase activity, and thus APP metabolism, though the specific mechanism for this regulation is not fully understood. Methods: To better understand the specific contributions of the various components of the

MAP Kinase pathway in ␥-secretase function and APP metabolism, we have used an established model of ␥-secretase in the developing Drosophila eye. We have examined the effect of genetic disruption of MAP Kinase pathway components on the phenotype of this AD model. Results: We report here that the subcellular localization of MAP Kinase, and regulation of the expression of the MAP Kinase transcription factor Pointed (Elk-1) are important for ␥-secretase activity in this AD model. Conclusions: Our results suggest that the subcellular localization of MAP Kinase, and those factors that regulate this localization, are important for APP processing, and may therefore be significant in AD pathogenesis. P1-057

DENDRITIC ALTERATIONS IN LAYER II/III PYRAMIDAL NEURONS IN THE FRONTAL CORTEX OF HTAU MICE DURING DISEASE PROGRESSION

Dara L. Dickstein, Patrick R. Hof, Mount Sinai School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background: Neurofibrillary tangles (NFTs) are composed of insoluble, hyperphosphorylated aggregates of the microtubule-associated protein Tau and are considered a hallmark of Alzheimer’s disease (AD). Mutations in the tau gene have been linked to NFT formation in a number of tauopathies; however, no tau mutations have been implicated in AD. Interestingly, the distribution and number of NFT deposits correlate with neuronal loss, synapse loss, and the degree of cognitive impairment observed in AD. Recently, mice that express all 6 isoforms of non-mutant human tau (htau) were generated. These mice undergo an age-related accumulation of phosphorylated tau and NFTs in the somata of neurons and exhibit neuronal death as early as 3 months of age. Here we use the hTau mice to investigate the morphological changes that occur in dendritic architecture and spine density during disease progression at 3, 6, and 12 months of age. Methods: Mice were perfused and intracellular injections of Lucifer Yellow were made in layer II/III pyramidal neurons of the frontal cortex. 3D reconstructions were performed on apical and basal dendritic segments for the determination of dendritic features. Results: We found that there was an ⬃20% decrease in apical dendritic arbor length between 3 and 6 month old mice; however no significant differences were observed in basal arbor length or branching pattern. In contrast, there was an ⬃ 30% increase in apical dendritic arbor length in 12 month mice compared to the other age groups. Conclusions: The findings above suggest that tau-related pathology induces morphological alterations in apical dendrites. The increase observed in 12 month mice may be due to the loss of affected neurons in this region leaving mainly intact neurons. Such irregularities in apical dendrites may result in the deterioration of neuronal function observed in AD and shed light on the mechanistic relationship between synaptic integrity and cognitive decline. In light of the dendritic aberrations, we are assessing spine density and morphology in these animals as well assessing neuronal loss in this region. P1-058

THE NEURONAL X11␣ ADAPTOR PROTEIN IMPROVES COGNITIVE FUNCTION OF Tg2576 (APPSWE) MICE

Darran M. Yates1, Jacqueline C. Mitchell1, Belall Ariff1, John Stephenson1, Christopher C. J. Miller1, Declan M. McLoughlin2, 1 MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry, London, United Kingdom; 2Dept of Psychiatry, Trinity College Dublin, St Patrick’s Hospital, Dublin, Ireland. Contact e-mail: [email protected] Background: X11␣/Mint1 is a neuronal adaptor protein that binds APP and modulates its processing, reducing A␤ production. Compared with single transgenic Tg2576 (APPswe) animals, double transgenic mice overexpressing X11␣ and APPswe have reduced cerebral A␤ loads and amyloid deposition. The present study examined whether memory deficits exhibited by Tg2576 mice could also be ameliorated by X11␣ overexpression. Methods: Transgenic mice overexpressing X11␣ were crossed with