Age-related impairments of proteasome activity and neuronal ubiquitinated iclusions in aging mouse brain

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A perturbation in ubiquitin-proteasome pathway plays a critical role in the accumulation of abnormal proteins in various neurodegenerative disorders. We studied neuronal cytoplasmic ubiquitinated inclusions that primarily affected the limbic system of SAMP10 (P10), a mouse model of cerebral degeneration, and age-related changes in brain proteasome activity in P10 using SAMR1 (R1) as a control. Based on ubiquitin-immunostained brains sections, the rate of inclusion-bearing neurons increased with aging relatively rapidly in P10. Ubiquitinated inclusions were densely distributed in the diagonal band, septum, accumbens, amygdala, hypothalamus, medial thalarnus, ventral hippocampus, subiculum and piriform, entorhinal, insular and cingulate cortices. Fluorogenic peptide substrate assays of tissue homogenates prepared from the limbic system revealed that proteasome activity of P10 at 3,7,12 and 17 months was respectively 181,105,82 and 48 (pmol AMC/min/mg protein) and that of R1 was respectively 150,134,126 and 88. Therefore, aging P10 mice develop neuronal inclusions in the limbic system because ubiquitinated abnormal proteins accumulate due to a decrease in proteasome activity.