PPID CONTROLS TOXIC AMYLOID FORMATION THROUGH PROLINE ISOMERIZATION

Abstract

Controlling the toxicity of pathogenic amyloidogenic proteins, like tau in Alzheimer's disease, is key to the prevention of many neurodegenerative diseases. PPID, a peptidyl-prolyl isomerase (PPIase), which we have shown to interact with tau, suppresses aggregation across several biological models. Recombinant PPID and P301L tau were combined and aggregation observed by Thioflavin T (ThT) fluorescence for 72 hours. Human HEK cells overexpressing P301L tau were transfected with PPID and sarkosyl insoluble tau levels quantified by Western blot. rTg4510 mice (n=8), overexpressing human P301L tau, were injected with AAV9-PPID or AAV9-GFP and tau species levels were measured by Gallyas silver-staining, and Western blots. Neuronal count was measured by unbiased stereology after tissue was stained with NeuN. PPID significantly reduced the aggregation of P301L tau in in vitro. Insoluble tau levels were significantly reduced in HEK cells after PPID transfection. Injection of AAV9-PPID into mouse hippocampi significantly decreased the production of insoluble tau and was neuroprotective compared to control. PPID can significantly lower insoluble tau levels across several models including mice overexpressing human tau. This provides the novel PPIase as a promising therapeutic target.