Miriam Goras

NPC Defects in Alzheimer’s Disease:Investigating NUP153, -93, and -214 Mislocalization in Hippocampal Neurons

Presented By Miriam Goras, Arizona State University (Undergrad)

Alzheimer’s disease (AD) is a progressive, neurocognitive disorder characterized by memory dysfunction and the presence of senile (Aβ) plaque and neurofibrillary tangles (composed of phosphorylated tau) [1]. Even though research efforts have contributed insights into the biology of AD, the underlying pathways mediating the cognitive decline are still not completely understood. Eukaryotic cells rely on the movement of proteins between the nucleus and cytoplasm which occurs through the nuclear pore complex (NPC). Nuclear pore complexes (NPC) contain approximately 30 different types of nuclear pore proteins known as nucleoporins (NUPs) that serve as selective barriers between the nucleus and cytoplasm [2]. Mutations in nucleoporin genes have been linked to various human diseases including neurological, nephrotic, cardiac, and neurodegenerative diseases [4]. A recent study showed miss-localization of nucleoporins in AD with direct phosphorylated-tau interaction [8]. Particularly, the report found mislocalization of NUP98 and NUP62 to the cytoplasm, often colocalizing with phosphorylated-tau and suggesting the depletion of NUPs from the nuclear envelope and potentially the direct interaction of phospho-tau [7]. These changes are consistent with NPC deterioration and nuclear-cytoplasmic transport defects [7]. However, this study only investigated four nucleoporins is ill-equipped to make conclusions regarding global changes to the NPC in AD that contribute to AD nuclear dysfunction to pathophysiology. Understanding how NPC subunits, specifically nucleoporins 153, 214, and 93 are affected in AD will expand our understanding of AD cell function and inform therapeutic advances. Immunohistochemistry was performed on glycol-fixed 40-micron sections of brain tissue and stained with DAB. Imaging of the CA1 region of the hippocampus at 40x magnification was used to find the optical density of neuron cells using opensource image analysis software ImageJ. Increased presence of NUP214 in both the nucleus and cytoplasm and presumptive neurotransmitter bundles in AD hippocampal neurons (figure 2). Elevated amount of NUP93 in the nucleus of AD but not ND hippocampal neurons (figure 3). Nuclear localization of NUP153 in AD but not ND (figure 4). Significantly greater optical density of NUP214 and NUP153 in AD compared to ND hippocampal neurons. Unclear whether these NUPs colocalize with phosphorylated tau and promote tau aggregation over the course of the disease (figure 5). This study showed the mislocalization of cytoplasmic NUP 214 in the cytoplasm, inner ring NUP 93 in nucleus, and suggested aberrant localization of inner basket NUP 153 in the nucleus in AD. A subsequent study is also being implemented to explore NUP intracellular localization in relation to MC1 pathological tau conformation which will inform early diagnostic advances and drug target therapy.

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