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Alzheimer’s disease (AD) is a neurodegenerative syndrome with high prevalence in the elderly population and whose early symptoms include impairment in spatial memory. Inherited forms of AD can be caused by dominant, single missence mutations in the Amyloid Precursor Protein (APP) gene, and this has been used to generate several animal models for the disease by overexpression of a mutated version of the protein. We have established at our institute a breeding colony of transgenic mice expressing the London mutation of APP as a transgene (APP[V717I]), and tested them at three and six months of age on the Morris Water Maze to confi rm a previous report on their impairment in the acquisition of this particular task. Moreover, APP[V717I] mice were used as a model to determine whether treatment with the tripeptide RER, a compound that has previously been shown to ameliorate amyloidinduced amnesia in young chicks, is capable of modifying their performance in the maze in a way that compensates the defi cits in spatial memory derived from the expression of the transgene. This work was supported by Grant #88 provided by the Alzheimer’s Society.
Cdk5 is a neuronal kinase involved in synaptic plasticity and memory formation. When overactive, Cdk5 can induce cell cycle arrest, tau hyperphosphorylation and apoptosis. This dichotomy in function is correlated with the degree of Cdk5 activation by small regulators. P25 is the most potent activator of Cdk5, absent in neurons under physiological conditions but induced during neuronal insults. In mouse models, high levels of p25 lead to neurodegeneration. Consistently, aged mice with life long exposure to low p25 levels exhibit tau hyperphosphorylation. However, expression of low p25 levels can improve learning in a sex-specifi c manner in young adult mice. The underlying molecular mechanisms of this dose effect are still poorly understood. Therefore, in the project presented we have undertaken comparative proteomics on hippocampal synaptosomes from wildtype and p25 mutant mice of both sexes. Four different approaches of tandem mass tag labeling were employed. From more than 500 quantifi able proteins, we identifi ed sex-specifi c changes in the p25 transgenics compared to wildtype mice. Selected proteins will be introduced and implications for the role of Cdk5-p25 in memory and neurodegeneration will be discussed. This work was supported by an MRC PhD studentship.
Alpha calcium and calmoduline-dependent kinase II (CaMKII) is the major protein in glutamateric neurons in the forebrain. Its activity is regulated by autophosphorylation on the threonine 286. CaMKII-T286A mutant mice have severe defi cits in context memory formation. They form fear memory of the context in fear conditioning task only after very intensive training with 5 shocks. Here we present the data showing that foreground fear conditioning training does not induce expression of any of the analysed immediate early genes (c-Fos, Zif268, Nur77 or JunB) in CaMKII-T286A mutant mice. Furthermore, long-term fear memory in the mutants cannot be blocked by administration of mRNA or protein synthesis inhibitors (actinomycin D or anisomycin) into dorsal hippocampus. Moreover, as revealed by Illumina microarrays, fear memory training does not induce context-shock association specifi c expression in the hippocampus. On the other hand, the training of the CaMKII-T286A mutant mice induces in the hippocampus expression of locally-translated proteins, Arc and PSD-95. In addition, both training-induced PSD-95 expression and long-term fear memory can be blocked by intrahippocampal administration of rapamycin (inhibitor of mammalian target of rapamycin kinase, the main regulator of local translation). Thus, our data strengthen the notion that local translation of PSD-95 in the dorsal hippocampus is the mechanism of long-term memory formation in the absence of alpha CaMKII autophosphorylation.
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