miRNA-Driven Mitochondrial Dysfunction in Alzheimer’s Disease - Project Summary Alzheimer’s disease (AD) is the leading cause of dementia worldwide, yet there is no effective treatment to slow or halt its progression. AD is characterized by the accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, inflammation, and dysfunction of brain-supporting cells. Recent studies suggest that microRNAs (miRNAs), small molecules that regulate gene expression, play a critical role in AD pathology. Our research focuses on miRNA PC-5P-12969, a newly identified miRNA that may influence disease progression by affecting key pathways related to GSK3α and APP, two proteins involved in neuronal damage and AD progression. Our long-term goal is to determine whether miRNA PC-5P-12969 can serve as both a biomarker for early diagnosis and a potential therapeutic target for AD. To achieve this, we propose the following aims: Aim 1.1: Validate miRNA PC-5P-12969 as a biomarker in human AD samples. We will measure miRNA PC-5P-12969 levels in blood, cerebrospinal fluid (CSF), and postmortem brain tissue from individuals with and without AD, using samples from diverse cohorts (TARCC and NIH NeuroBioBank). We will analyze its correlation with cognitive decline, Aβ pathology, and tau pathology to assess its diagnostic potential. Aim 1.2: Investigate the mechanistic role of miRNA PC-5P-12969 in regulating GSK3α and APP. Using iPSC-derived neurons from AD patients and healthy controls, we will examine how miRNA PC-5P-12969 affects the expression of GSK3α and APP and its impact on mitochondrial function and synaptic integrity. Aim 2: Determine the protective effects of miRNA PC-5P-12969 in an AD mouse model (APP NL-G-F Knock-in). By increasing miRNA PC-5P-12969 levels in AD mice, we will evaluate its impact on memory function, Aβ accumulation, and mitochondrial health, exploring its therapeutic potential. Our preliminary data suggest that miRNA PC-5P-12969 is elevated in AD brain tissue and can reduce GSK3α and APP expression, potentially protecting neurons from disease-related damage. By validating its role as both a biomarker and a therapeutic target, this study could lead to earlier AD diagnosis and novel treatment approaches. This project has the potential to advance our understanding of AD and contribute to the development of new diagnostic tools and therapeutic strategies to improve patient outcomes.
