Toxic Effects of Extracellular Tau Oligomers on Neurons


One of the many insults that neurons often suffer in Alzheimer’s disease (AD) brain is that their nuclei, which normally have a relatively smooth surface marked by an occasional shallow invagination, develop multiple deeper invaginations that make the nuclei look “raisinlike.” Because a neuron’s genes reside in its nucleus, it is possible that this physical alteration of nuclear structure is accompanied by gene expression changes that contribute to the conversion of normal neurons into AD neurons. We now would like to test that possibility, as well as define molecular 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 “non-Alzheimer’s tauopathies,” but it also exists as small aggregates, or oligomers, both inside neurons and in extracellular space. To determine whether any gene expression changes also are caused by xcTauOs, we will use tandem RNA-Seq and Ribo-Seq. RNA-Seq will provide a comprehensive picture of neuronal mRNA, which is made from DNA in the genes, whereas Ribo-Seq catalogs which mRNAs actually direct synthesis of the proteins they encode. 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.

Funding to Date



Studies of Tau, Translational


George S. Bloom, Ph.D.