Extracellular Competing Endogenous RNA Networks Reveal Key Regulators of Early Amyloid Pathology Propagation in Alzheimer’s Disease

Extracellular vesicles (EVs) are small capsular bodies released by cells, mediating
responses in intercellular communication. The role of EVs in Aβ pathology spreading in the
Alzheimer’s disease (AD) brain has been evidenced, although whether this occurs due to
the co-transportation of Aβ peptides or contribution of other factors, such as EV-associated
transcripts, remains uncertain. In vitro studies of miRNA cargo in neuron-derived extracellular
vesicles (NDEVs) show that Aβ hyperexpression alters the transcriptomic profile;
however, it is not clear to what extent this causes changes at the organ level. By utilizing
datasets from published studies, we generated competing endogenous RNA (ceRNA) networks
for miRNAs co-expressed in NDEVs and the brain in different stages of pathology,
using both an APP overexpressing neuronal model (in vitro) and brain cortices from 6- and
9-month-old APP/PSEN1 mice (in vivo). Networks integrating information from mRNAs,
lncRNAs, and circRNAs showed two candidate lncRNAs (Kcnq1ot1 and Gm42969) and a
circRNA (Pum1), while enrichment analyses detected that NDEVs miRNAs signal to other
CNS cells and that this signal can be disrupted by Aβ pathology, contributing to the loss of
long-term potentiation seen in early AD.