Stefan Prokop - US grants

In order to support the goals of the 1Florida Alzheimer?s Disease Research Center (1Florida ADRC) the Neuropathology Core will perform diagnostic evaluations and quantitative analyses of the brains collected from deceased individuals that participate in the clinical studies. A definite diagnosis of AD still requires a thorough post-mortem evaluation. We will coordinate storage of biospecimens including blood plasma, serum, DNA, and CSF and their distribution in response to request from qualified investigators inside and outside the 1Florida ADRC. The specific aims of the Neuropathology Core are: Aim 1 Conduct a thorough post-mortem CNS examination in accordance to National Institute on Aging-Alzheimer?s Association consensus guidelines of ~25 ADRC subjects/year followed longitudinally in the Clinical Core with consent and establish a neuropathological diagnosis for each patient. Aim 2 Provide neuropathologic data to be included in the database using support from the Data Management and Statistical (DMS) Core and provide ADRC data in concert with the Clinical Core. Neuropathological data will be provided to the National Alzheimer Coordinating Center (NACC) through the Data Management and Statistical Core Aim 3 Collect and maintain a bank of archived unfixed frozen and fixed tissue, DNA, cerebrospinal fluid (CSF), serum and plasma from ADRC patients with AD, MCI, preMCI or other related neurodegenerative diseases, along with CN controls and distribute these samples to qualified investigators within the ADRC and external investigators upon request. Aim 4 Be responsive to changing needs in tissue acquisition and processing to support new scientific studies and provide consultation regrading appropriate experimental design for neuropathology studies in both human samples and mouse models of various inclusion pathologies relevant to neurodegenerative disorders. Aim 5 Execute clinical pathologic case conferences, brain cutting and other activities supporting research training activities and ensure integration with other Cores within the 1Florida ADRC. Final diagnoses will be achieved by clinical-pathological consensus conferences to be held quarterly with the Clinical Core, which will serve as an important educational component that will integrate with the Research Education Component. These activities of this Core are all critical functions of an ADRC.

Summary Compelling data support a contemporary version of the amyloid cascade hypothesis (ACH) as a valid framework both for understanding AD pathogenesis and the development of disease modifying therapeutics. However, key aspects of the ACH are not well understood. One such aspect is the relationship between accumulation of aggregated A? and neurodegeneration. The mainstream concepts regarding this relationship are that aggregates of A? are directly neurotoxic and/or trigger a toxic glial response. However, numerous observations indicate that the link between A? accumulation and neurodegeneration may be more complex. As a working hypothesis and a non-exclusive mechanism to the direct A? aggregate ?toxin? model, we propose that a large number of biologically active proteins that we will refer to as amyloid associated proteins (AAPs) accumulate in the brain as A? deposits. Thus, A? aggregate accumulation may not be sufficiently toxic to induce downstream neurodegeneration unless accompanied by AAP accumulation. Indeed, in this scenario accumulation of AAPs helps to trigger the neurodegenerative phase of AD, accounting for the long delay between onset of A? deposition and neurodegeneration in humans. The proposed studies will leverage extensive data from the AMP-AD initiative and other published studies that has used state of the art proteomics to identify a large number of candidate AAPs that are increased both in AD and mouse models of A? deposition. Many of these candidate AAPs have known or inferred cell-signaling functions. Further, for some candidate AAPs there is either previous data demonstrating that they are associated with AD or we have generated novel data showing accumulation in senile plaques. Finally, as shown by others for the AAPs, ApoE and clusterin, we find that expression of select AAPs (midkine, pleiotrophin) modulates amyloid deposition. Building off this preliminary data, we propose three aims that are designed to probe our global hypothesis. In Aim 1 we will evaluate the spatiotemporal accumulation of AAPs in AD and in mouse models of amyloid deposition. In Aim 2 we will use rAAV- mediated expression of the AAPs in APP mouse models to a) further evaluate the association with amyloid plaques, b) determine if expression alters amyloid deposition and influences other AD relevant pathologies independent of effects on A?. In Aim 3 we intend to explore the mechanisms by which the AAP associates with the plaque and how that association might alter the biological properties of the AAP.