Abstract

Alzheimer’s disease (AD) is the leading cause of age-related dementia, continuing to escalate in prevalence and societal cost this century. Efforts to develop effective treatments thus far have been hindered by insufficient understanding of the molecular mechanisms of disease.

A hallmark of AD is the pathological accumulation of protein tau in neurons, however its cause and role in disease is unknown. RNA is found within pathological tau in AD brains and suggested to induce tau accumulation. Meanwhile, there is emerging evidence of tau-mediated RNA dysregulation in AD, possibly affecting important genes for neuron function and survival. Excitingly, recent studies by our lab and others have independently made connections between tau accumulation and a particular type of RNA, known as N6-methyladenosine-modified RNA (m6A-RNA). However, the nature and causality of their relationship in AD are unclear – whether m6A-RNA induces tau accumulation or tau dysregulates m6A-RNA of genes critical for neuron health.

To understand how this potentially harmful interaction leads to disease, I will 1) sequence and identify m6A-RNA associated with tau in AD patient brains, 2) study how m6A-RNA affects tau accumulation in human neurons, and 3) visualize the physical interaction between m6A-RNA and tau molecules. My proposed research will use cutting-edge molecular biology techniques to reveal how tau accumulation and m6A-RNA cooperate to drive disease, pinpointing new therapeutic targets for AD and related dementias.