Defining Pathological Roles of Novel Protein Interactions with Amyloid in Alzheimer's Disease

About This Grant

Despite extensive research, the mechanisms through which Aβ aggregates contribute to cellular and tissue dysfunction in Alzheimer’s Disease (AD) are still debated. This debate, centered on mechanisms of toxicity, also extends to other human amyloidoses. Though most efforts have focused on identifying toxic species or conformers (e.g., oligomers, protofibrils, fibrillar conformers) and the effects of these Aβ only assemblies, our latest findings propose an alternative, non-mutually exclusive hypothesis. Based on comprehensive proteomic analyses of human AD and control brains, along with mouse models of amyloid deposition, we have proposed the Amyloid Scaffold Hypothesis (ASH). This hypothesis suggests that the accumulation of numerous proteins, scaffolded by, and dependent on amyloid formation, represents a critical mechanism driving downstream pathophysiology in AD. Unlike traditional views of amyloid assembles as direct toxins, the ASH posits that amyloid-associated protein accumulation underpins disease progression. To explore this hypothesis, we will i) determine the molar abundance of proteins co-accumulating with Aβ in AD and Aβ-depositing mouse model brains and assess whether this correlates with changes in protein solubility ii) investigate the interactions driving protein co-accumulation with amyloid deposits, focusing on Aβ, amyloid, and heparan sulfate proteoglycans and iii) test whether extracellular accumulation of these co-aggregating proteins, in the absence of amyloid, induces downstream pathophysiologic changes like those seen in AD. These studies are highly significant. They will directly test a novel mechanism by which amyloid may mediate pathophysiologic effects and may provide clues as to normal physiologic associations of Aβ. Though focused on AD, this work could also have implications for other amyloidoses. This work integrates data and tools from AMP-AD, TREAT-AD, and MODEL-AD initiatives, and is supported by rigorous findings from published and unpublished studies.