O4‐11‐03: Interaction between the ubiquitin proteasome system, autophagy and progressive tauopathy in vivo

Abstract

Neurodegenerative diseases including Alzheimer's Disease (AD) and the tauopathy known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) are characterized with intracellular inclusions of misfolded proteins. Downregulation and dysfunction of either the ubiquitin-proteasome system (UPS) or the autophagic-lysosomal system (A-LS) that clear misfolded proteins and maintain cellular function have been vastly reported in the development of these diseases. Macroautophagy (autophagy), a major degradative pathway of the lysosomal system, plays a significant role in the removal of protein aggregates that are too large, or that cannot be unfolded by chaperone proteins and that are consequently unable to be degraded by the UPS. We hypothesize that in the early stages of tauopathy the UPS is down regulated and is unable to efficiently clear misfolded/ubiquitinated tau species, thus the system becomes overwhelmed as larger aggregates of tau accumulate. We envisage that the A-LS is then upregulated in an effort to compensate for the lost UPS activity and to clear the aggregates, but ultimately both systems fail resulting in accelerated pathology. To investigate the interplay between UPS and A-LS functioning with tau accumulation we use in vivo, ex vivo (acute organotypic slices) and brain homogenate studies of the young and old rTg4510 line that expresses the P301L mutant tau transgene at high levels and develop robust pathology. We demonstrate that accumulation of hyper-phosphorylated tau precedes elevation of ubiquitinated proteins and induction of autophagy markers. The decline in proteasome activity correlates with accumulation of tau aggregates. Additionally, we show that administration of the phosphodiesterase 4 inhibitor, rolipram, elevates proteasome activity, reduces tau levels and improves cognitive performance in rTg4510 mice with mild pathology. In advanced pathology, activation of proteasome failed to reduce tau levels and improves cognitive performance. Our data support the view that tau aggregates perturb the function of UPS in a time-dependent manner and induce autophagy, but insufficiently to clear the aggregates. Moreover, pharmacologic elevation of proteasome activity in vivo and ex vivo of rTg4510 mice reduces tau levels and improves cognitive performance, suggesting a novel therapeutic approach to treat tauopathy disorders including AD and FTD.