My lab utilized a novel strategy to produce a triple transgenic model of Alzheimer's disease (AD). Rather than using a crossbreeding approach, we directly inserted two transgenes (human -beta APP/Swe and -tau P301L) into the genome of homozygous PS1M146V knocking mice. This novel strategy produces several unique and significant advantages compared to other approaches: (i) Because the tau P301L and beta APPSwe transgenes were microinjected into embryos from PS1M146V mice, the triple transgenic are on the same genetic background, thereby eliminating genetic heterogeneity. (ii) Both transgenes integrated at the same genetic locus and, therefore, will not independently assort in subsequent generations; likewise the M146V mutation is knocked-in to the PS1 gene, and this allele will also not assort in future generations. Consequently, our triple transgenic mice breed as easily as """"""""single"""""""" transgenic mice, a significant advantage for colony management and for introducing additional transgenes into this line. (iii) A large colony of triple transgenic mice can be easily and efficiently generated. In contrast, crossbreeding strategies for generating multi-transgenic genotypes are labor intensive, require extensive genotyping, and result in a low proportion of mice with the desired genotype. (iv) The triple transgenic mice have been bred to homozygosity, which doubles the expression levels, and also further facilitates colony management and breeding. Our triple transgenic mice develop a progressive, age-related AD-like phenotype that includes both both Abeta and tau pathology, synaptic dysfunction, deficits in long term potentiation, and impaired memory-related performance in the Morris water maze, a hippocampal-dependent task of spatial memory. The broad goal of this proposal is to identify and correlate genetic interactions that underlie neuronal and synaptic dysfunction in our triple transgenic mice.
In aim 1, we will perform a detailed molecular and neuropathological characterization of the triple transgenic mice and determine how various gene interactions (e.g., tau alone, tau + APP, etc.) influence the development of AD neuropathology.
In aim 2, we will determine if the synaptic dysfunction is age-related, identify molecular determinants (e.g., soluble vs. insoluble Abeta, tau hyperphosphorylation) and gene interactions (tau, PS1, or APP) that underlie the synaptic dysfunction.
In aim 3, we will determine if calcium dyshomeostasis underlies the synaptic dysfunction and propose to develop a novel transgenic mouse the expresses a calcium indicator protein (inverse pericam) in neurons.
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