Protein aggregation underlies most or all types of neurodegeneration and many other age-progressive diseases. We have isolated and analyzed very pure aggregates from Alzheimer?s Disease (AD), Parkinson?s Disease (PD); nematode models of Huntington?s Disease (HD), AD, and PD; and human cell-culture models of AD. The proteins that contribute to these aggregates show considerable overlap; for example, >80% of proteins that are significantly more abundant in aggregates from AD than from age-matched controls, are shared and concordant in amyloid plaque (containing A?1-42) and in neurofibrillary tangles containing hyperphosphorylated tau), although these aggregates have long been thought to be exclusively extracellular and intra-neuronal, respectively. We recently performed novel cross-linking studies that defined the protein interfaces that mediate adhesion within aggregates, and have screened drugs for their ability to disrupt protein coalescence in vivo. Several drugs have the ability to reduce or slow aggregate accrual, and one (PNR502) has been shown to reverse aggregation in both mouse and nematode models of AD-like amyloidosis. We are currently in the process of performing quantitative structure-activity studies to enable the generation of 2nd-generation drugs, further optimized for desirable drug properties. Two patents have been filed (with both VA and affiliated-university participation) for subsets of active drugs; the first of these addresses PNR502 and several of its structural analogs.
This research is highly relevant to the healthcare of veterans, who comprise an aging population with elevated incidence of traumatic brain injury (TBI). Both age and TBI increase the risk of AD, PD, and other neurodegenerative diseases. By seeking basic principles that govern protein aggregation across many neuropathies, we hope to gain insights and develop novel interventions (e.g., drugs) that apply to diverse neurological pathologies including ?orphan diseases? that are too rare or underfunded to attract substantial research effort aimed at their prevention or cure.
