Evidence for aggregation-independent, PrP ^C -mediated Aβ cellular internalization

Abstract

Evidence linking amyloid beta (Aβ) cellular uptake and toxicity has burgeoned, and mechanisms underlying this association are subjects of active research. Two major, interconnected questions are whether Aβ uptake is aggregation-dependent and whether it is sequence-specific. We recently reported that the neuronal uptake of Aβ depends significantly on peptide chirality, suggesting that the process is predominantly receptor-mediated. Over the past decade, the cellular prion protein (PrPC) has emerged as an important mediator of Aβ-induced toxicity and of neuronal Aβ internalization. Here, we report that the soluble, nonfibrillizing Aβ (1–30) peptide recapitulates full-length Aβ stereoselective cellular uptake, allowing us to decouple aggregation from cellular, receptor-mediated internalization. Moreover, we found that Aβ (1–30) uptake is also dependent on PrPC expression. NMR-based molecular-level characterization identified the docking site on PrPC that underlies the stereoselective binding of Aβ (1–30). Our findings therefore identify a specific sequence within Aβ that is responsible for the recognition of the peptide by PrPC, as well as PrPC-dependent cellular uptake. Further uptake stereodifferentiation in PrPC-free cells points toward additional receptor-mediated interactions as likely contributors for Aβ cellular internalization. Taken together, our results highlight the potential of targeting cellular surface receptors to inhibit Aβ cellular uptake as an alternative route for future therapeutic development for Alzheimer’s disease.

Dynamic Changes in the Levels of Amyloid-β42 Species in the Brain and Periphery of APP/PS1 Mice and Their Significance for Alzheimer’s Disease

“…These processes are coordinated by transmitting sensory signals from the periphery to the central nervous system, allowing communication from the intestine to the brain via the "gut-brain axis" (Brierley et al, 2018). Foley et al (2020) have confirmed that soluble Aβ 42 Ms and Aβ 42 Os could be absorbed by neurons and enter the intestine along the vagus nerve. Therefore, there is a strong correlation between the colon and degenerative neurological disease.…”

“…Presently, several potential mechanisms of how brain Aβ is released into peripheral tissues have been mentioned. Some convincing evidence suggests that brain-derived soluble Aβ 42 Ms and Aβ 42 Os can be absorbed by neurons and enter the intestine along the vagus nerve (Foley et al, 2020). In contrast, the administration of Aβ 42 into the gastrointestinal tract may induce amyloidosis in the central nervous system (CNS) and AD-related pathologies, such as dementia (Sun et al, 2020).…”

Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies

“…Although not assessed here, it appears likely that sPrP may act similarly against other proteinopathies, given the central role of PrP C as neuronal toxicity receptor ( 8 , 11 , 15 ). It would also be interesting to assess whether sPrP bound to these oligomers and deposits may serve as an “eat-me” signal for internalization by phagocytic cells ( 74 ). In sum, stimulation of PrP C shedding may be a promising therapeutic target in neurodegenerative diseases, yet further studies on this are clearly required.…”

A crystal-structural study of Pauling–Corey rippled sheets

“…Peptides with mixed chirality may be used to access frameworks with unique properties, including protease-resistant peptide drugs, 1,2 hydrogels with enhanced rigidity, 3,4 aggregation blockers, 5,6 amyloid oligomer-to-fibril converters, 7,8 and mechanistic tools. 9,10 Mirror-image proteins may also be used to enhance crystallization of proteins that are hard to crystallize, sometimes by creating unique interactions between the protein enantiomers. [11][12][13][14] A systematic incorporation of D-amino acids into proteins and peptides is expected to give access to a huge structure-function space that cannot be accessed in any other way.…”