Project Summary/Abstract The parent R01 of this supplement is investigating the role of Parkinson’s disease (PD) pathology in the periphery, specifically in the enteric nervous system (ENS). The rationale for these studies is the fact that peripheral pathology (in the form of aggregated alpha-synuclein (α-syn)) is hypothesized to be linked both to gastrointestinal (GI) dysfunction as well as being the source of pathology that eventually leads to neurodegeneration in the brain. Our initial findings have confirmed that ENS α-syn pathology does cause GI symptoms; however, we were unable to find evidence of a direct transfer of pathology to the brain (i.e. via “prion-like” transfer). However, we are now investigating whether the ENS pathology can afflict the brain in a “paracrine” fashion; for instance, via enhanced inflammation originating from the ENS. In this supplement we propose that the same premise holds true for AD-related pathologies of the periphery (e.g. tau, amyloid precursor protein(APP)). To that end, our central hypothesis states that induction of enteric AD pathology will result in systemic inflammation that exacerbates neurotoxicity in rodent models of AD neurodegeneration. Interestingly, investigations into AD-related pathologies of the ENS are extremely rare. The reason for this is likely stemming from the fact that GI dysfunction is not a reported prodromal symptom in AD. This does, however, not necessitate the absence of ENS pathology in AD. In fact, Aβ-immunoreactive plaques have been reported in human AD patients, and ENS pathology is found in transgenic animals. We propose that any such peripheral pathology will induce systemic inflammation, a condition which can predispose or sensitize central neurons to degeneration. Inflammation, once thought to be a consequence of neurodegeneration, is becoming increasingly thought of as having a causative role in AD neurodegeneration. However, we still do not understand what exactly triggers neuroinflammation, and have yet to understand the temporal relationship between inflammation and neurodegeneration. Herein we will utilize a novel gene therapy method developed for the parent R01 whereby we will overexpress AD-related proteins specifically in neurons of the ENS. A crucial aspect of this approach is that transgene expression is spatially restricted to enteric neurons and temporally controlled. This will allow us to specifically study the role of ENS pathology in disease, without the confound of ubiquitous expression that can be found in transgenic animals, or following systemic delivery of AAV. At the same time, we will also utilize AAV to overexpress disease related proteins in the CNS. With this approach we expect to find 1) An increase in markers of systemic inflammation, 2) An increase in indices of neuroinflammation, and 3) Increased susceptibility to disease proteins such as mutant tau or APP in central neurons. If any of these outcomes are proven true, it will demonstrate that changes in the PNS can contribute to CNS disease, laying the foundation for a novel area of AD research. Moreover, if we can demonstrate that non-cell autonomous factors contribute, or even trigger, neurodegeneration, a significant focus moving forward will be to better understand exactly where in the molecular process of neuronal loss that neuroinflammation plays a contributory role.

Project Narrative The aim of this supplement is to investigate the causal relationship between peripheral Alzheimer’s disease (AD) related pathologies on systemic inflammation and central nervous system degeneration. The prevailing view on the processes that lead to neuron death in AD states that protein aggregation is directly toxic to neurons in the brain, however, we propose that AD-related pathology in the periphery (e.g. gut) may trigger inflammation that renders the brain sensitive to insults. We propose to utilize gene therapy to define the (pathological) role of AD pathology in enteric nervous system, and thereby potentiate the discovery of novel therapeutic targets for the treatment of this devastating disorder.