Adipocyte-Derived Small Extracellular Vesicles from Patients with Alzheimer Disease Carry miRNAs Predicted to Target the CREB Signaling Pathway in Neurons

Rachael A. Batabyal, Center for Genetic Medicine, Children's National Hospital, Washington, DC 20012, USA.
Ankush Bansal, Center for Neuroscience Research, Children's National Hospital, Washington, DC 20010, USA.
Laura Reck Cechinel, Center for Genetic Medicine, Children's National Hospital, Washington, DC 20012, USA.
Kayla Authelet, Center for Genetic Medicine, Children's National Hospital, Washington, DC 20012, USA.
Madeleine Goldberg, Center for Genetic Medicine, Children's National Hospital, Washington, DC 20012, USA.
Evan Nadler, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
C Dirk Keene, Department of Pathology, University of Washington, Seattle, WA 98104, USA.
Suman Jayadev, Department of Neurology, University of Washington, Seattle, WA 98104, USA.
Kimiko Domoto-Reilly, Department of Neurology, University of Washington, Seattle, WA 98104, USA.
Gail Li, Department of Psychology and Behavioral Sciences, School of Medicine, University of Washington, Seattle, WA 98104, USA.
Elaine Peskind, Department of Psychology and Behavioral Sciences, School of Medicine, University of Washington, Seattle, WA 98104, USA.
Kazue Hashimoto-Torii, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Dedra Buchwald, Institute for Research Education to Advance Community Health, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA.
Robert J. Freishtat, Center for Genetic Medicine, Children's National Hospital, Washington, DC 20012, USA.

Document Type

Journal Article

Publication Date

9-13-2023

Journal

International journal of molecular sciences

Volume

24

Issue

18

DOI

10.3390/ijms241814024

Keywords

EVs; adipose tissue; dementia; exosomes; obesity

Abstract

Alzheimer disease (AD) is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, synaptic dysfunction, and progressive dementia. Midlife obesity increases the risk of developing AD. Adipocyte-derived small extracellular vesicles (ad-sEVs) have been implicated as a mechanism in several obesity-related diseases. We hypothesized that ad-sEVs from patients with AD would contain miRNAs predicted to downregulate pathways involved in synaptic plasticity and memory formation. We isolated ad-sEVs from the serum and cerebrospinal fluid (CSF) of patients with AD and controls and compared miRNA expression profiles. We performed weighted gene co-expression network analysis (WGCNA) on differentially expressed miRNAs to identify highly interconnected clusters correlating with clinical traits. The WGCNA identified a module of differentially expressed miRNAs, in both the serum and CSF, that was inversely correlated with the Mini-Mental State Examination scores. Within this module, miRNAs that downregulate CREB signaling in neurons were highly represented. These results demonstrate that miRNAs carried by ad-sEVs in patients with AD may downregulate CREB signaling and provide a potential mechanistic link between midlife obesity and increased risk of AD.

Department

Pediatrics

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