Toxic Effects of Extracellular Tau Oligomers on Neurons

One of the insults that neurons suffer in Alzheimer’s disease (AD) is that their nuclei, which normally are smoothly surfaced, develop multiple deep invaginations that make them look “raisinlike.” Because a neuron’s genes reside in its nucleus, it is possible that this alteration of nuclear structure is accompanied by gene expression changes that contribute to the conversion of normal neurons into AD neurons. We will test that possibility and define mechanisms responsible for forming misshapen neuronal nuclei. We already have an exciting clue about how neuronal nuclei invaginate: they form in cultured neurons within an hour of the cells’ exposure to extracellular tau oligomers (xcTauOs). Tau is the protein that forms neurofibrillary tangles in AD and other “tauopathies,” but it also exists as small aggregates, or oligomers, both inside neurons and extracellularly. To determine whether gene expression changes are caused by xcTauOs, we will use RNA-Seq and Ribo-Seq, which respectively provide a picture of total mRNA, which is made from DNA in the genes, and which mRNAs actually are making proteins. Our experimental systems will include cultured neurons with and without xcTauO exposure, and transgenic mice known to harbor tau oligomers. In this manner, we should be able to identify neuronal genes and proteins whose levels are altered by xcTauOs and, using big data tools, identify biochemical pathways that are associated with and may cause nuclear deformation and pathogenic gene expression. By extension, such genes and proteins represent potential targets for preventing or delaying AD symptom onset or slowing symptom progression.