mRNA and circRNA mislocalization to synapses are key features of Alzheimer's disease.

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. This resulted in the discovery of hundreds of mislocalized mRNAs in AD among frontal and temporal brain regions. Similar observations were found in an APP^swe/PSEN1^dE9 mouse model. Furthermore, major differences were observed among circular RNAs (circRNAs) localized to synapses in AD including two overlapping isoforms of circGSK3β, one upregulated, and one downregulated. Expression of these distinct isoforms affected tau phosphorylation in neuronal cells substantiating the importance of circRNAs in the brain and pointing to a new class of therapeutic targets. Author summary: Synaptic plasticity is the foundation for cognition and describes the process by which synaptic connections between neurons are formed, strengthened, or weakened based on signals transmitted by neighboring neurons. Essential to this process is the ability of synapses to respond rapidly to signals and restructure their morphology by translating proteins from a pool of localized mRNAs which is orchestrated by a complex cytoskeletal trafficking system. Given that synapse loss is a cardinal feature of Alzheimer's disease (AD), we RNA sequenced fractionated synaptic particles from brain samples from AD patients and healthy controls to determine whether RNA localization to synapses is impacted in AD. We discovered hundreds of mislocalized mRNAs as well as circular RNAs (circRNAs) which are non-coding isoforms shown to play critical regulatory roles in the brain. Among our data, we discovered two isoforms of circGSK3β, one upregulated, and one downregulated in AD. Expression of these isoforms in neuronal culture was shown to affect tau phosphorylation, dysregulation of which is a hallmark of AD. These findings point to RNA localization and circRNAs as key components to understanding AD pathology and implicate new targets for AD therapies. [ABSTRACT FROM AUTHOR]