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P1–066: Aberrant ubiquitin impairs learning and memory in transgenic mice by partial inhibition of the proteasome
Author(s) -
Van Leeuwen Fred W.,
Tijn Paula,
Hobo Barbara,
Hol Elly M.,
Fischer David F.
Publication year - 2006
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.2006.05.441
Subject(s) - proteasome , ubiquitin , transgene , genetically modified mouse , striatum , biology , ubiquitin ligase , microbiology and biotechnology , chemistry , biochemistry , neuroscience , gene , dopamine
commonly recognized cause of early onset FAD and account for more than half of the autosomal dominant FAD cases (Lleo et al, 2004). Methods: We generated a mouse expressing the entire human PS1 transcription unit (including promoter, enhancers, 13 exons, introns) which also contains the M146V mutation. Mice containing the PAC clone expressed human PS1 and did not express murine PS1. These mice were then assessed for neuropathological features of AD. The brains were stained with Nissl and an anti-tubulin antibody to identify neurons and dendrites respectively. Neuron counts were obtained stereologically using a computer-assisted microscopy system and StereoInvestigator software (MicroBrightField). Results: Here we show evidence of neuronal degeneration indicated by condensed chromatin within the nucleus and loss of cytoplasm. There was an approximate 42% decrease in neuronal numbers within the PS1 M146V transgenic mice compared to wildtype controls. Moreover, neurons within the transgenic group were in an advanced degenerative state. We also show evidence of dendritic abnormalities in the neocortex of 8 month old animals. In light of these data, we are assessing dendritic morphology as well as spine density and morphology using DiOlistic technology with 3D reconstruction at high resolution, and spinophilin immunostaining. Conclusions: These results validate this transgenic system as an authentic animal model of FAD and define essential roles of presenilins in synaptic plasticity, learning and memory, and neuronal survival in the adult brain.