Reduced free ubiquitin levels and proteasome activity in cultured neurons and brain tissues treated with amyloid beta aggregates.

Neurodegenerative diseases are characterized by progressive cognitive decline and the loss of neurons in the central nervous system; many are also characterized by abnormal aggregation of misfolded proteins. Ubiquitin (Ub) is a eukaryotic protein that plays pivotal roles in protein degradation and cellular signaling. Ubiquitinated aggregates are observed in neurodegenerative diseases; this ultimately results in reduced levels of available or free Ub. However, it remains unclear whether neurotoxicity arises from the aggregates or a deficiency of free Ub. To investigate this, we treated primary neurons of mouse embryonic brains with amyloid beta (Aβ) 42 and found that free Ub levels were decreased and cell viability was reduced in Aβ42-treated neurons. As reduced levels of free Ub are closely related to impaired function of the proteasome, we evaluated proteasome activity and found that proteasome activity was reduced upon treatment of primary neurons and mouse brain slices with Aβ42. Therefore, we conclude that proteotoxic stress from Aβ42 treatment reduced the levels of available Ub and decreased proteasome activity, resulting in inflammatory stress and apoptosis of neurons.