Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons

Sonia Podvin, Alexander Jones, Qing Liu, Brent Aulston, Charles Mosier, Janneca Ames, Charisse Winston, Christopher B. Lietz, Zhenze Jiang, Anthony J. O'Donoghue, Tsuneya Ikezu, Robert A. Rissman, Shauna H. Yuan, Vivian Hook

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2 Scopus citations

Abstract

The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer's disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. Notably, exosomes from human-induced pluripotent stem cell (iPSC) neurons expressing the AD familial A246E mutant form of presenilin 1 (mPS1) are capable of inducing tau deposits in the mouse brain after in vivo injection. To gain insights into the exosome proteome cargo that participates in propagating tau pathology, this study conducted proteomic analysis of exosomes produced by human iPSC neurons expressing A246E mPS1. Significantly, mPS1 altered the profile of exosome cargo proteins to result in (1) proteins present only in mPS1 exosomes and not in controls, (2) the absence of proteins in the mPS1 exosomes which were present only in controls, and (3) shared proteins which were upregulated or downregulated in the mPS1 exosomes compared to controls. These results show that mPS1 dysregulates the proteome cargo of exosomes to result in the acquisition of proteins involved in the extracellular matrix and protease functions, deletion of proteins involved in RNA and protein translation systems along with proteasome and related functions, combined with the upregulation and downregulation of shared proteins, including the upregulation of amyloid precursor protein. Notably, mPS1 neuron-derived exosomes displayed altered profiles of protein phosphatases and kinases involved in regulating the status of p-tau. The dysregulation of exosome cargo proteins by mPS1 may be associated with the ability of mPS1 neuron-derived exosomes to propagate tau pathology.

Original languageEnglish (US)
Pages (from-to)13033-13056
Number of pages24
JournalACS Omega
Volume6
Issue number20
DOIs
StatePublished - May 25 2021
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by the NIH grant R56AG057469 (awarded to R.A.R., V.H., and T.I.), NIH R01NS094597 and R01NS109075 (awarded to V.H.), and ITN start-up funds to S.H.Y. A.J. was supported by NIH T32GM007752 (awarded to J. H. Brown), and C.B.L. was supported by NIH T32MH019934 (awarded to D. Jeste).

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