Amyloidosis associated proteins in Alzheimer’s disease pathogenesis
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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 Aβ and neurodegeneration. The mainstream concepts regarding this relationship are that aggregates of Aβ are directly neurotoxic and/or trigger a toxic glial response. However, numerous observations indicate that the link between Aβ accumulation and neurodegeneration may be more complex. As a working hypothesis and a non-exclusive mechanism to the direct Aβ 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 Aβ deposits. Thus, Aβ 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 Aβ 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 Aβ 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 Aβ. 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.
