Toxic effect of pathogenic tau on the nucleus

The nuclear envelope is a lipid bilayer that encases the genome and provides a physical boundary between the cytoplasm and the nucleoplasm. While the nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope, the smooth exterior can be interrupted by tubular invaginations of the nuclear envelope into the deep nuclear interior. Such structures are termed the "nucleoplasmic reticulum." Increased frequency of nuclear envelope invagination occurs in disease states including various cancers, viral infections, and laminopathies, a group of heterogeneous disorders that arise due to mutations in the gene encoding lamin A. A significant increase in the frequency of nuclear envelope invaginations in the human Alzheimer's disease brain has recently been reported. Nuclear envelope invaginations are caused by pathogenic tau, one of the two major pathological hallmarks of Alzheimer's disease. Pathogenic tau-induced dysfunction of the lamin nucleoskeleton drives nuclear envelope invagination and consequent accumulation of polyadenylated RNA within invaginations, both of which drive neuronal death. Our ongoing studies suggest that maintaining proper cytoskeletal, nucleoskeletal, and genomic architecture are critical for survival and function of adult neurons.