CELF2 as a context-dependent RNA regulator in Alzheimer’s Disease

Neurodegenerative diseases such as Alzheimer’s disease (AD) arise from complex interactions between genetic risk, age-related molecular changes, and dysregulated RNA processing. While genome-wide studies have identified numerous AD-associated loci, the RNA-based mechanisms that translate genetic risk into disease phenotypes remain incompletely understood. RNA-binding proteins (RBPs) are emerging as critical post-transcriptional regulators linking genomic information to neuronal function. CELF2 is a multifunctional RBP that controls alternative splicing, mRNA stability, and translation, yet its role in aging and neurodegeneration has not been defined.

Here, we investigate CELF2 as a neurogenetic regulator in AD using an amyloid-driven mouse model. We demonstrate that CELF2 undergoes a pronounced age- and disease-dependent subcellular localization shift, transitioning from predominantly nuclear localization in young brains to increased cytoplasmic accumulation in aged and AD-like states. This redistribution is accompanied by enhanced colocalization with stress granules, suggesting engagement with stress-responsive RNA regulatory pathways. These findings indicate that disease-associated changes in CELF2 localization fundamentally alter its functional role, shifting it away from canonical nuclear splicing regulation.

To assess the functional consequences of CELF2 dosage in AD, we examined mice with partial reduction of CELF2 expression in the disease background. Behavioral analyses revealed significant improvements in cognitive performance relative to AD controls. At the molecular level, reduced CELF2 attenuated pathological alternative splicing of key AD-associated genes, including APP and MAPT, restoring splice patterns toward a non-pathological state. In parallel, lipidomic profiling revealed increased abundance of myelin-associated lipid species, consistent with improved white matter integrity and neuronal resilience. These molecular changes were accompanied by reduced neuropathological burden.

Together, these findings identify CELF2 as a context-dependent RNA regulator linking genetic risk, aging, and post-transcriptional dysregulation in AD. We propose a model in which stress-induced relocalization of CELF2 represents a key regulatory switch in neurodegeneration, and that excessive CELF2 activity exacerbates pathological RNA processing. Importantly, modest reduction of CELF2 rebalances RNA regulation, improves myelin lipid homeostasis, and preserves cognitive function. This work positions CELF2 as a novel RNA-centric modifier of neurodegenerative disease and highlights RNA-based regulation as a promising avenue for precision medicine and therapeutic intervention in aging-related neurological disorders.

Ishana Syed is a PhD candidate in Biomedical Sciences (Neuroscience discipline) at UT Health San Antonio. Her research focuses on RNA-based mechanisms underlying neurodevelopment and neurodegeneration, with particular emphasis on the RNA-binding protein CELF2 in Alzheimer’s disease. Using integrative approaches spanning genomics, splicing analysis, lipidomics, and behavior, her work investigates how age- and disease-associated RNA dysregulation contributes to cognitive decline. Ishana is also interested in translational neuroscience, precision medicine, and RNA-targeted therapeutic strategies for neurological disorders.