Abstract Body

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, Aβ aggregate accumulation may not be sufficiently toxic to induce downstream neurodegeneration unless accompanied by accumulation of other proteins (amyloid associated proteins (AAPs) in the plaque. Indeed, AAPs could help trigger the neurodegenerative phase of AD, accounting for the long delay between onset of Aβ deposition and neurodegeneration in humans. We have 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 AAPs have known or inferred cell-signaling functions. Further, for some candidate AAPs there is either previous data demonstrating that they are AD AAPs 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 and promote dramatic shifts to CAA. These data reveal the complexity of the proteinopathy in AD, and provide the field a novel framework in which to conduct future studies.