Heat shock proteins (HSPs) promote the correct folding and refolding of misfolded proteins, including tau, amyloid-β, and α-synuclein, and are therefore attractive targets for a number of neurodegenerative diseases. Several approaches to target HSP70 and HSP90 were presented. Allen Reitz (ALS Biopharma, USA) identified hit compounds that lowered tau levels by inducing HSP70 expression in human glioblastoma cell lines. Understanding the mechanism of action of a target is vitally important during drug design. This point was highlighted by Chad Dickey (University of South Florida, USA), who discovered that inhibition of HSP70 ATPase activity could also be effective at stabilizing disorganized tau. Inhibitors from a HTS based on rhodacyanine dyes have now been validated for their ability to decrease tau accumulation and rescue long-term potentiation in hippocampal slice cultures from Tg4510 tau mice. A second member of the heat shock family, HSP90, was the focus of Gabriela Chiosis's (Memorial Sloan Kettering Cancer Center, USA) drug discovery program. Chiosis identified two populations of HSP90 in pathogenic or stressed tissue (tumors and dystrophic neurons); a good housekeeping HSP90 complex and an HSP90 complex that selectively binds to pathogenic protein. Hsp90 inhibitors developed by this team specifically bind the pathogenic HSP90 complex and reduce total tau and phospho-tau following acute treatment in the 3× FAD transgenic mouse model. Chronic studies will be required to assess behavioral outcomes.
Dysfunctional protein degradation pathways contribute to neurodegeneration. Karen Duff (Columbia University, USA) provided target validation for autophagy and proteasome targets demonstrating that mice with progressive tauopathy show a decline in proteasome function concomitant with an induction of autophagy and accumulation of fibrillar tau aggregates. In vivo induction of autophagy following acute oral administration of trehalose, a non-reducing dissacharide, effectively decreased tau pathology in the P301L tau mouse model. Duffnoted that the decreased proteosomal function seen during the onset of pathology could be reversed pharmacologically, highlighting both autophagy and proteasome activation as two potential drug targets in stimulating clearance of protein aggregates that present in numerous neurodegenerative diseases.
Lysosomal function plays a critical role in protein clearance. Lysosomal storage diseases, such as Gaucher disease, Fabry disease and Sandhoff disease, show evidence of accumulated intraneuronal amyloid-β in addition to decreased lysosome enzyme function. Brandon Wustman (Amicus Therapeutics, USA) and team have developed a set of novel pharmacological chaperones that enhance the activity of critical lysosomal enzymes, are orally available, cross the BBB, and are currently in phase III for Fabry disease. Now, Wustman and team are testing a novel, potent pharmacological chaperone for its effects in clearing intraneuronal amyloid-β in an animal model of cerebral amyloid angiopathy, an orphan indication with relevance to AD.
Additional strategies at the proof-of-concept stage targeted protein aggregates through immunotherapy. Rakez Kayed (University of Texas, USA) has developed an oligomer immunotherapy agent, TOMA (tau oligomer monoclonal antibody), that effectively reduced tau pathology following intracerebroventricular injection in the P301L tau mouse model. In the plenary session, Ryan Watts (Genentech, USA) demonstrated that β-site APP cleaving enzyme (BACE) monoclonal antibodies engineered to cross the BBB via the transferrin receptor effectively reduced BACE activity and amyloid-β levels without affecting total BACE expression in an AD mouse model.