Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease.

Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies.

Studying tau protein propagation and pathology in the mouse brain using adeno-associated viruses.

The progressive spread of pathological brain lesions containing aggregated tau protein is a hallmark of Alzheimer's disease and other neurodegenerative diseases. In AD, this process follows a distinct pattern along neuronal connections from the entorhinal cortex to hippocampal areas and further on through the limbic system. In other tauopathies, the spread of tau appears less hierarchical throughout the brain, and also nonpathological tau is reported to cross-synaptic connections in the brain. To be able to study the process of cell-to-cell transport of tau and the associated neurotoxicity in the brain in vivo, adeno-associated virus-mediated expression of tau can be used to express different forms of tau in distinct brain areas in rodent models. As an example, we describe how the expression of FTD-mutant human tauP301L in the entorhinal cortex of wild-type mice can be used to study the propagation of tau to connected neurons and to determine pathological consequences such as tau hyperphosphorylation, misfolding, and gliosis. The approach described can easily be translated to study other aggregating and/or propagating proteins in the brain such as synuclein, Abeta, or SOD1.