tRNA fragments and their role in tau pathology in Alzheimer's disease and tauopathies

About This Grant

Project Summary Alzheimer’s disease (AD) and related dementias (ADRD) pose significant challenges with a growing societal impact. Addressing these challenges requires comprehensive research into the neurobiology of the diseases, leading to innovative biomedical concepts, approaches, and molecular targets. A central factor in these disorders is the protein tau, whose misregulated homeostasis, aggregation, and intercellular spread contribute to AD, Frontotemporal dementia (FTD), and other tauopathies. Tau-containing neurofibrillary tangles (NFTs) from AD brains are known to contain RNA, and it is proposed that tau-RNA interactions may facilitate tau aggregation and modulate neuronal vulnerability to stress. However, the specific RNA species involved in tau pathology remain unidentified. Our data suggest a novel class of small RNA transcripts—tRNA-derived fragments (tRFs)—that accumulate in AD, potentially binding tau and promoting its misfolding and aggregation. Regulated by disease-related neuronal stress, tRFs are enriched in extracellular spaces and body fluids, including cerebrospinal fluid (CSF), and can be taken up by recipient neurons. Our research aims to investigate the role of specific tRFs in tau aggregation, pathology propagation, and neurodegeneration in ADRD through the following Specific Aims. Specific Aim 1: Characterize the small RNA landscape, with a focus on tRFs, at different stages of AD pathology using an optimized RNA sequencing platform. Examine the RNA binding capacity of intracellular and extracellular tau variants and mutants using human induced pluripotent stem cell (iPSC)-derived neurons and rodent primary neurons. Identify tRFs within pathological tau aggregates and visualize their colocalization with tau pathology in human AD brains. Specific Aim 2: Investigate the impact of selected tRFs and tRF-enriched extracellular complexes on tau homeostasis and pathology using gain- and loss-of-function approaches in neuronal cell models. Specific Aim 3: Examine the effects of specific tRFs on tau pathology and behavioral phenotypes in WT mice and a humanized Tau P301S/PS19 mouse model of tauopathy and neurodegeneration. Assess neuroprotective effects of targeting specific tRFs in the brain. This collaborative R01 project seeks to unravel the complex molecular mechanisms underlying ADRD and explore the cellular and extracellular biology of these disorders. Findings may reveal a new class of potential therapeutic targets and biomarkers.