Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s-like pathology in mouse and fly APP overexpression models

Abstract

The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD). We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal-specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT-based proteasome-activating peptidomimetics that stably penetrated the blood-brain barrier and enhanced 20 S /26 S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models. The protective effects of proteasome overexpression appear to be driven, at least in part, by the proteasome’s increased turnover of the amyloid precursor protein along with the prevention of overall proteostatic dysfunction.

Orthogonal approaches required to measure proteasome composition and activity in mammalian brain tissue

“…Collectively, these studies conclude that there is a link between proteasome function in the nervous system and its potential contribution to the pattern and severity of cognitive decline observed in AD and possibly other neurodegenerative disorders ( 1 , 21 , 39 , 40 ). As a result of the conclusions made from these studies, an emerging effort has been to find new ways to activate proteasomes with the hope of slowing down or reversing some of the demise of brain disease observed across various neurodegenerative disorders ( 41 , 42 , 43 ). Despite a considerable effort to understand proteasome biology, deep insight into the composition and activity of proteasomes in the mammalian nervous system and human brain diseases has been limited to only a few measurements and at times single assays.…”

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

“…S3, F and H), perhaps as a mechanism to regulate inflammatory response ( 60 ) or to promote new synapses ( 61, 62 ). Cluster 8 was related to proteasomal functions and these genes were upregulated with hAD-tau, suggesting a compensatory mechanism aimed at clearing protein aggregates ( 63–65 ); at 21 DIV, expression of these genes was relatively diminished with AAV.ACSS2, suggesting a potential regulation of proteasomal pathways by AAV.ACSS2 ( Fig. 3, C and D and fig S3M).…”

Relationships between protein degradation, cellular senescence, and organismal aging

“…Remarkably, these benefits extend to mice with neuron-specific overexpression of the 20S CP subunit β5 in the AD mouse model. Furthermore, a newly developed peptide that allosterically enhances proteasome activity inhibited cell death and cognitive decline in fly and mouse models of AD ( 40 ) .…”