Adipocyte-Derived Small Extracellular Vesicles from Patients with Alzheimer Disease Carry miRNAs Predicted to Target the CREB Signaling Pathway in Neurons
International journal of molecular sciences
EVs; adipose tissue; dementia; exosomes; obesity
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.
Batabyal, Rachael A.; Bansal, Ankush; Cechinel, Laura Reck; Authelet, Kayla; Goldberg, Madeleine; Nadler, Evan; Keene, C Dirk; Jayadev, Suman; Domoto-Reilly, Kimiko; Li, Gail; Peskind, Elaine; Hashimoto-Torii, Kazue; Buchwald, Dedra; and Freishtat, Robert J., "Adipocyte-Derived Small Extracellular Vesicles from Patients with Alzheimer Disease Carry miRNAs Predicted to Target the CREB Signaling Pathway in Neurons" (2023). GW Authored Works. Paper 3410.