Pathological and genetic studies of cerebral degeneration in senescence-accelerated mouse

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Following findings were obtained through the studies using SAMP 10 (senescence-accelerated mouse), a spontaneous model of cerebral degeneration.1. Ubiquitinated intraneuronal inclusions that affects chiefly the limbic structuresMany neurons had ubiquitinated inclusions in the brains of aged SAMP10 mice. These inclusions were different from those previously reported, but showed a similar pattern of distribution as that of neurofibrillary tangles.2. Age-related neuronal intranuclear DNA damagesTUNEL positivity of neuronal nuclei increased with advancing age in the prefrontal cortex and limbic structures in SAMP 10 mice. These TUNEL positive neurons were not apoptotic. This DNA damage was considered as a manifestation of degenerative changes associated with neuronal atrophy.3. Synaptic loss with agingRegional specificity of degenerative changes in the neuropil of SAMP10 mice was determined by quantifying synapse-related proteins. Synapses were lost from the frontal cortex by more than 50% in aged SAMP10 mice.4. Age-related changes in the dendritic complexity of prefrontal neuronsApical but not basal dendrites of the prefrontal neurons in SAMP10 mice gradually retracted toward the somata with relative preservation of dendritic complexity. The dendritic spines were lost as well.5. Creation of a large-scale colony of cross-bred miceSAMP10 mice were cross bred with SAMR1 mice, and F_1 and F_2 mice were raised up to age 16 months. Learning and memory function and brain morphology were evaluated in all of these mice. Microsatellite markers were proven to be useful to perform QTL anaysis.