The Role of Small RNAs in Alzheimer's Disease

We aim to describe changes in small RNA species in brain, CSF and plasma to understand the role of small RNAs in Alzheimer’s Disease and develop predictive models. In aim 1 we will generate small RNA sequences in brain, CSF and Plasma of individuals with Alzheimer’s Disease and Controls. Then, we will use statistical and bioinformatic tools to 1) Describe and understand changes in small RNA proportions and species between cases and controls; and 2) Generate a model that allows disease prediction. In aim 2, we will use neuron-derived induced pluripotent stem cells to investigate the effects of specific small RNAs on the amyloid-beta pathway to understand if small RNAs are part of the causal pathway.

Small RNAs short molecules of RNA that regulate gene expression. MicroRNAs are the most known and studied type of small RNAs. However, other families of sRNAs exist and are, in fact, more abundant than Micro RNAs. In the context of Alzheimer disease, only micro RNAs have been investigated, especially for their potential as biomarkers. Even though many candidates have been proposed, only a few of them have been identified by more than one study. In consequence, the relationship between Alzheimer disease and small RNAs is mostly unknown. In this proposal, we will characterize the different populations of small RNAs in brain, plasma and cerebrospinal fluid of individuals with Alzheimer disease. Then we will investigate their biological role by: i) identifying which small RNAs are different between cases and controls in each tissue (brain, plasma and cerebrospinal fluid); ii) use small RNAs to generate tools that allow disease prediction, and iii) use cellular models to investigate the biological consequences of dysregulating the identified small RNAs.

Small RNAs (sRNAs) are short (12-200nt) non-coding regulatory RNAs that balance gene expression. In Alzheimer disease (AD), most of the studies have focused on micro RNAs (miRNAs), but miRNAs are not the most abundant sRNA species in tissues and biofluids. Thus, the relationship between AD pathophysiology and sRNAs beyond miRNAs is mostly unknown and the aim of the present proposal.

In this study, one of the aims is to find a set of small RNAs that is specific enough to help in the detection and diagnosis of Alzheimer’s Disease (AD). The delivery of a specific and cost-effective diagnostic tool will require further research, but at the completion of this study, we aim to propose a set of small RNAs useful to diagnose Alzheimer’s Disease.