For nearly 20 years, our Program has been at the leading edge of discoveries addressing the consequences of neuroinflammation triggered by neuronal stresses arising from genetic factors (mutation and other alleles), traumatic brain injury, epileptiform activity, corruption of angiotensin, insulin/IGF1 and autophagy systems, and normal aging. The resulting knowledge of key early events and predisposing factors in neuropathogenesis, together with new collaborative opportunities, now position this Program to turn the page and embark on novel translational studies. We have documented neuroinflammation-particularly elevation of interleukin 1 (IL-1) - to be a principal driver of overexpression of pathology-related proteins. For example, in humans with Down's syndrome, epilepsy, HIV infection, Alzheimer's, and Parkinson's, as well as in rodent models and neural cultures, neuronal stress leads to overexpression of APP and sAPP for induction of glial activation and IL-1. Production of A? and other proteins that are prone to aggregation (e.g., ?-synuclein and hyperphosphorylated tau) follow suit. These proteins disrupt or overwhelm the ubiquitin-proteasome system (UPS) leading to proteinopathy that includes aggregation of motor proteins and elements of the UPS. In Project 3, we have begun to characterize this proteinopathy through identification of a novel protein that contributes critically to age-related aggregation of components of the UPS in A?-transgenic nematodes (C. elegans), a phenomenon eradicated by non-steroidal anti-inflammatory agents and other, and novel drugs. This is lent additional relevance by the Project-1 discovery that ?-synuclein, hyperphosphorylated tau, and Parkin (the E3 ubiquitin ligase for these two proteins) co-aggregate in AD and PD. Insulin resistance and related effects on metabolism, uncovered in Project 2, are likely related to such proteinopathies and their inflammatory sequelae. We propose that these three elements-neuroinflammation, proteinopathy, and insulin resistance-cause and/or reinforce one another to create neurodegeneration that is characterized by glial activation, IL-1 overexpression, and protein aggregates with overlapping constituents regardless of the specific disease classification. A corollary is that common targets can be identified leadin to development of therapeutic drugs to reduce aggregation of disease-related proteins and proteinopathy in neurological diseases. The proposed studies are constructed to identify, explore, and functionally characterize specific pathways responsible for pathologic signatures that are either unique to one disease or are common to several age-related neurological diseases. Such delineation may identify tractable processes amenable to specific drug interventions and suggest lifestyle/environmental conditions that foster successful aging. The addition of a new drug-discovery effort (Core D) empowers us to test the over-riding hypothesis while simultaneously identifying lead compounds of therapeutic potential. Thus, the arc of this Program is now directed toward effective therapies, based on foundations laid through mechanistic research proposed here and conducted throughout the productive history of this Program.
Overall This Program Project Grant will study Alzheimer's disease and related disorders through a multi-discipline approach that integrates three different projects: one devoted to the analysis of the pathological characteristics of human aging-related brain disorders, one that will elucidate connections between Alzheimer's and type-2 diabetes, and one that will use nematodes to discover the components and the triggers for protein clumping in neurodegenerative diseases. All of these projects will be supported by four Core facilities, including one that will execute state-of-the art drug discovery efforts. Together, this Program aims to achieve a novel and powerful advancement toward not only the understanding of brain diseases of the elderly, but also their successful treatment.
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