Prion protein oligomers cause neuronal cytoskeletal damage in rapidly progressive Alzheimer\u2019s disease

Mohsin Shafiq,Saima Zafar,Inga Zerr,Berta Puig,Aneeqa Noor,Isidre Ferrer,Jakob Matschke,Markus Glatzel,Neelam Younas,Hermann Clemens Altmeppen,Matthias Schmitz

doi:10.1186/s13024-021-00422-x

Abstract

BackgroundHigh-density oligomers of the prion protein (HDPs) have previously been identified in brain tissues of patients with rapidly progressive Alzheimer’s disease (rpAD). The current investigation aims at identifying interacting partners of HDPs in the rpAD brains to unravel the pathological involvement of HDPs in the rapid progression.MethodsHDPs from the frontal cortex tissues of rpAD brains were isolated using sucrose density gradient centrifugation. Proteins interacting with HDPs were identified by co-immunoprecipitation coupled with mass spectrometry. Further verifications were carried out using proteomic tools, immunoblotting, and confocal laser scanning microscopy.ResultsWe identified rpAD-specific HDP-interactors, including the growth arrest specific 2-like 2 protein (G2L2). Intriguingly, rpAD-specific disturbances were found in the localization of G2L2 and its associated proteins i.e., the end binding protein 1, α-tubulin, and β-actin.DiscussionThe results show the involvement of HDPs in the destabilization of the neuronal actin/tubulin infrastructure. We consider this disturbance to be a contributing factor for the rapid progression in rpAD.

Highlights

High-density oligomers of the prion protein (HDPs) have previously been identified in brain tissues of patients with rapidly progressive Alzheimer’s disease
A total of six interactors were identified, either uniquely present in rapidly progressive Alzheimer’s disease (rpAD)-specific high density factions (HDFs) or commonly shared by rpAD and sporadic Creutzfeldt-Jakob disease (sCJD) subtypespecific HDFs, whereas the high density PrPC oligomers (HDPs) interactomes of controls and Sporadic AD (spAD) subtypes had no common interactors with rpAD
Some of the HDP interactors from rpAD HDFs were commonly found as the interactors of HDP conformers from sCJD subtypes

Summary

Introduction

High-density oligomers of the prion protein (HDPs) have previously been identified in brain tissues of patients with rapidly progressive Alzheimer’s disease (rpAD). A study from Abu Rumeileh et al (2017) reported a remarkably higher CSF tau level in rpAD cases (median = 1223 pg/mL, n = 44) compared to that of spAD (median = 697 pg/mL, n = 45) [13, 14]. We described the presence of high molecular weight oligomers of the cellular prion protein (PrPC) in the frontal cortex, in patients with a rapidly progressive form of AD [8]. The physiological relevance of the prion protein oligomers consistently identified in the brains of rpAD patients has not been explored

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