Soluble oligomeric species of the amyloid-β (Aβ) peptide exhibit pronounced neurotoxic effects in Alzheimer’s disease. Recent studies have indicated that the prion protein (PrP) is one of the cell-surface receptors, so-called a bad receptor, of Aβ oligomers that mediates downstream cellular toxicity. A rational classification of Aβ oligomers on the basis of conformation indicates that there are two distinct types of oligomers, namely, prefibrillar and fibrillar oligomers that are positive to A11 and OC conformation-dependent antibodies, respectively. The mechanism of heterotypic assembly of conformationally distinct oligomers and PrP is poorly understood. In this work, using an array of biophysical and biochemical tools, we dissect the molecular mechanism of the interaction of A11- and OC-positive Aβ42 oligomers with human PrP. Using site-specific binding titrations, we show that the recruitment of Aβ oligomers primarily occurs via the electrostatic interaction between the N-terminal intrinsically disordered region of PrP and Aβ oligomers. Our results demonstrate that OC-positive fibrillar oligomers possessing in-register parallel β-sheet packing displayed ∼30 times stronger binding with PrP compared to A11-positive oligomers. We also show that these OC-positive oligomers exacerbate their toxic effects on mammalian cells upon binding to PrP. On the contrary, the addition of PrP does not alter the toxicity exhibited by A11-positive oligomers. Our findings suggest that strategies targeting the interaction between PrP and OC-positive oligomers, which have been shown to be highly concentrated in the vicinity of amyloid plaques, may have therapeutic potential against Alzheimer’s disease.

Soluble oligomers of amyloidogenic proteins like an amyloid-β (Aβ) peptide are believed to exhibit toxic effects in neurodegenerative diseases. The structural classification of oligomers indicates two fundamentally distinct oligomers, namely, fibrillar and prefibrillar oligomers that are recognized by OC and A11 conformation-specific antibodies, respectively. Previous studies have indicated that the interaction of Aβ oligomers with the lipid membrane is one of the mechanisms by which these oligomers exert their toxic effects in Alzheimer's disease. Here, we report that the orientational ordering of liquid crystals (LC) can be used to study the membrane-induced aggregation of Aβ oligomers at nanomolar concentrations. Our results demonstrate a faster fibrillation kinetics of OCpositive fibrillar Aβ oligomers with the lipid monolayer in comparison to that of the A11positive prefibrillar Aβ oligomers. Our findings suggest a general strategy for distinguishing conformationally distinct soluble oligomers that are formed by a number of amyloidogenic proteins on lipid-decorated aqueous−LC interfaces.

Amyloid fibrils are highly ordered nanoscopic protein aggregates comprising a cross-b amyloid core and are associated with deadly human diseases. Structural studies have revealed the supramolecular architecture of a variety of diseaseassociated amyloids. However, the critical role of transient intermolecular interactions between the disordered polypeptide segments of protofilaments in directing the supramolecular structure and nanoscale morphology remains elusive. Here, we present a unique case to demonstrate that interchain excitation energy migration via intermolecular homo-Fö rster resonance energy transfer can decipher the architecture of amyloid fibrils of human a-synuclein. Site-specific homo-Fö rster resonance energy transfer efficiencies measured by fluorescence depolarization allowed us to construct a two-dimensional proximity correlation map that defines the supramolecular packing of a-synuclein within the fibrils. These studies captured unique heteroterminal cross talks between the fuzzy interprotofilament interfaces of the parallel-in-register amyloid spines. Our results will find applications in discerning the broader role of protein disorder and fuzziness in steering the distinct polymorphic amyloids that exhibit strain-specific disease phenotypes.

The accumulation of toxic soluble oligomers of the amyloid-β peptide (Aβ) is a key step in the pathogenesis of Alzheimer’s disease. There are mainly two conformationally distinct oligomers, namely, prefibrillar...

Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformationspecific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl-D-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.