Peripheral Macrophage Signatures of Inflammation in Neurodegenerative Diseases

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DESCRIPTION (provided by applicant): Late onset Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative disorders that affect nearly six million Americans and are estimated to cost the United States economy over $100 billion annually. Unfortunately, current therapies and treatments are only symptomatic and these diseases remain relentlessly progressive. Thus, our need to fully understand the pathogenesis of these diseases and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and to our health care systems. Interestingly, while these diseases typically manifest clinically later in life, a variety of postmortem evidence suggests that the pathological hallmarks of both AD and PD, and by inference the disease itself, occur early in an individual's life. This has led to an emerging view of the disease whereby a set of disparate mechanistic triggers over a lifetime converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in either AD or PD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize AD and PD. Specifically, we propose that peripheral monocytes/macrophages are affected by early pathogenic processes, as well as may contribute to disease pathology, which will be reflected in alterations in transcript and protein levels and functions. As such, these changes will serve as important antecedent biomarkers for disease diagnosis and progression and should provide valuable insights into disease pathophysiology and potential therapeutics. We propose to use two murine models of these diseases, the triple transgenic model of AD (3xTg-AD) and the human wild-type synuclein transgenic model of PD (hSYN-WT+/+), which will allow us to collect tissues over the time course of each "disease." In Specific Aim 1 we will collect peripheral monocytes/macrophages from these transgenic mouse strains and wild type control mice and interrogate gene expression using microarrays at three time points. We will identify transcriptomic profiles that will be specific for each disease model (e.g. AD vs. PD vs. control) and that will be more generalizable to common neurodegenerative processes. In Specific Aim 2 we will test the specificity and sensitivity of these profiles in peripheral monocytes/macrophages isolated from human AD, PD, and control subjects. We hypothesize that the transcriptomic signatures identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD and PD. With the aging of America's "baby boomers" the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop easily accessible, robust, specific, and sensitive biomarkers of early AD and PD, which would greatly facilitate the diagnosis and treatment of these diseases.