Mislocalization of diverse RNA species to synapses in Alzheimer’s disease and aging

Abstract

The distribution of RNAs in neurons is non-random, and there are complex cellular mechanisms regulating the transport and localization of RNAs along neural projections to synaptic locations. This enables synapses to respond rapidly to synaptic signaling by synthesizing proteins from a pool of sequestered dormant mRNAs to alter synaptic strength, morphology, and connections. This phenomenon is called “localized translation” and is an essential mechanism facilitating plasticity in the brain and cognition. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by buildup of extracellular amyloid plaques and intracellular hyperphosphorylated tau neurofibrillary tangles in the brain followed by synapse and neuron loss and subsequent cognitive impairment. Previous studies of AD have revealed disruptions among cytoskeletal trafficking and RNA binding proteins which are essential for proper synaptic localization of RNAs. Differences in expression of non-coding RNAs including microRNAs and circRNAs, which serve regulatory functions in the expression of mRNAs, have also been observed. Therefore, it is likely mislocalization of RNAs to synapses is taking place in AD which would negatively impact the mechanism of localized translation and contribute to synaptic dysfunction in disease. Given how dynamic and finely regulated RNA localization is for neuronal function, it is also possible changes in localization are taking place across lifespan. In this thesis, I investigate differences in RNA localization, including mRNAs, microRNAs, and circRNAs, in AD by RNA sequencing synaptosomes from patient and control tissue. Synaptosomes are fractionated particles encapsulating synaptic material. We find substantial differences in mRNA localization, and we also find differences in circRNA isoforms present at synapses. There are also correlations between differential expression of microRNAs and target mRNAs mislocalized in AD. Finally, we discover changes in synaptic RNAs across lifespan in mouse models that suggest AD may represent an acceleration of age-related changes. This research adds a new dimension to our understanding of AD pathology and suggests new targets for therapeutic interventions.