Abstract

Cognitive decline in Alzheimer's Disease (AD) and many other age-related dementias have long been associated with the presence of insoluble amyloid plaques that disrupt normal synaptic functioning. However, recent studies have revealed that synapse impairment from AD is much more potently associated with soluble amyloid-β oligomers (aβo), rather than from insoluble fibrils. Soluble oligomers are able to adopt heterogeneous structures that are irregular and promiscuously bind to membrane proteins, thereby dysregulating downstream amyloid assemblies such as tau. Multiple screening methods have identified cellular prion protein (PrPc) as a putative target of aβo, and subsequent studies have confirmed a pathophysiological pathway in AD involving aβo-PrPc binding. However, aβ monomers and insoluble fibrils do not bind to PrPc, thus the disordered binding domain of PrPc can be used to isolate aβo assemblies. In order to exploit these interactions, we designed biomimetic PrPc peptides that complex soluble aβo in replica-exchange molecular dynamics simulations. While peptides are unlikely to act as AD therapeutics, they can help inform the types of side-chain interactions that drive soluble amyloid formation for use in next-generation therapeutics that cross the blood-brain barrier. Similarly, targeting aβo through disordered PrPc peptides can enable the tracking of soluble oligomers through fluorescent tagging during aβ fibril formation. To the extent possible, results are compared to solid-state NMR spectroscopy of aβo-PrPc complexes, where heterogeneous structures are identified. Taken together, this study highlights how small disordered peptides modulate pathological protein behaviors in AD and other degenerative diseases where soluble amyloid oligomers, rather than insoluble fibrils, drive cell toxicity.

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