mRNA and circRNA Mislocalization to Synapses are Key Features of Alzheimer’s Disease
Samuel N. Smukowski, Cassidy Danyko, Jenna Somberg, Eli J. Kaufman, Meredith M. Course, Nadia Postupna, Melissa Barker-Haliski, C. Dirk Keene, Paul N. Valdmanis
Abstract:
Proper transport of RNAs to synapses is essential for localized translation of proteins in response to synaptic signals and synaptic plasticity. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by accumulation of amyloid aggregates and hyperphosphorylated tau neurofibrillary tangles followed by widespread synapse loss. To understand whether RNA synaptic localization is impacted in AD, we performed RNA sequencing on synaptosomes and brain homogenates from AD patients and cognitively healthy controls.
Introduction:
Alzheimer’s disease (AD) is the most prevalent form of dementia and estimated to account for at least 50 million cases worldwide. The disease is characterized by extracellular accumulation of amyloid-β (Aβ) peptides into plaques and intracellular neurofibrillary tangles of hyperphosphorylated microtubule-associated protein tau (MAPT). AD can be separated into two types: familial (fAD) early-onset and late-onset sporadic (sAD) forms.
Materials and Methods:
Human brain tissue samples used in this study were derived from brains donated for research by participants in the UW ADRC and the Kaiser Permanente Washington (KPW) ACT study, including 11 donors with neuropathologically-confirmed AD dementia, and 12 cognitively healthy individuals with no or low AD neuropathologic change.
The UW ADRC is a mostly clinic-based study of participants with varying levels of cognitive impairment who are followed annually with a battery of neuropsychometric tests until they withdraw from the study or die, and most consent to donate their brains for research.
Discussion:
When a synapse is stimulated, rapid, local changes result in the activation of translational machinery on relevant, proximal RNAs. Past studies have established synaptic-localized transcriptomes in cell culture and healthy models. In this study, we sequenced the synaptic-localized transcriptomes of human brain tissue, and we discovered remarkable differences between AD patients and cognitively healthy, age-matched controls. We furthermore identified differences among different brain regions (frontal and temporal lobes), as well as differences from a popular mouse model of fAD.
Citation: Smukowski SN, Danyko C, Somberg J, Kaufman EJ, Course MM, Postupna N, et al. (2024) mRNA and circRNA mislocalization to synapses are key features of Alzheimer’s disease. PLoS Genet 20(7): e1011359. https://doi.org/10.1371/journal.pgen.1011359
Editor: Vincent Plagnol, University College London, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
Received: July 29, 2023; Accepted: July 2, 2024; Published: July 29, 2024.
Copyright: © 2024 Smukowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Mouse synaptosome data has been deposited in the NCBI Gene Expression Omnibus under accession number GSE237258.
Funding: This work was supported by grants from the Alzheimer’s Association (AARG-22-919611), the University of Washington Royalty Research Foundation (A153324), and National Institutes of Health National Institute of Aging (NIA) R21AG082032 to P.N.V. S.N.S is supported by a National Science Foundation Graduate Fellowship. In addition, the work is supported by the UW ADRC Neuropathology Core, which is funded by the NIA (P30 AG066509). This work was also supported by the ACT study (U19 AG066567) and the Nancy and Buster Alvord Endowment to C.D.K. M.B.H mice husbandry and samples were funded by National Institutes of Health R01AF067788. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
