Abstract Body

Utilizing network-modules derived from an extensive proteomic study of human Alzheimer’s disease (AD) brains and newly generated APP CRND8 mouse brain proteomic data, we show that many of the brain proteomic changes observed in AD are mimicked in mouse models with massive amyloid loads. Focusing on secreted matrix and signaling proteins that increased in AD and the aged APP mouse brain, we establish that many of these proteins are within amyloid plaques, present in cerebrovascular amyloid, accumulate in dystrophic neurites, increased in reactive astrocytes, or some combination of these. Some proteins are known or suspected heparan sulfate binding proteins, but many can be shown to bind fibrillar Aβ and AVS peptide amyloid fibril in vitro. Consistent with this data, midkine (MDK) and pleiotrophin (PTN) accumulate in transthyretin cardiac amyloid and MDK in pancreatic amylin amyloid. Overexpression of MDK and PTN in APP mice alters the spatiotemporal accumulation of Aβ driving dramatic increases in CAA. MDK, PTN and SMOC1 also influence kinetics of Aβ aggregation in vitro. These data establish that i) many proteomic changes observed in human AD can be attributed to amyloid deposition and ii) that amyloid structures can scaffold the co-accumulation of many signaling proteins. Further, for the first two proteins investigated, we show that overexpression alters Aβ amyloid deposition. These data reinforce the role of amyloid in AD and other disorders but suggest that downstream pathology induced by amyloid is incredibly complex and that important pathophysiologic changes may be mediated by other co-accumulating proteins. Indeed, perhaps rather than direct toxicity is it is the scaffolding function of amyloid which results in sequestration of numerous signaling molecules that truly drives the pathophysiologic cellular responses that lead to organ failure.