paired helical filaments

NFTs are intracellular fibrillar structures composed of aggregations of paired helical filaments (PHFs), which are made up of abnormally phosphorylated tau.

In PHFs, tau shows an abnormal and high level of phosphorylation localized at the C-terminus, which is associated with a loss of microtubule-binding capacity and a consequent accumulation in neuronal bodies.

Similarly, in FTDP-17, mutations at or near the region of the tau gene that encodes the microtubule-binding region are thought to be responsible for tau aggregation and the loss of motor function.

After aggregation, PHF-tau undergoes posttranslational modifications, including ubiquitination, glycation and oxidation.

PHF-tau is usually assumed to be a neurotoxic agent and several mechanisms have been suggested for its role in neurodegeneration.

First, because it has been shown that phosphorylated tau inhibits microtubule assembly and causes the disassembly of microtubules, PHF-tau is also thought to compromise microtubule stability and function, resulting in a loss or decline in axonal or dendritic transport in disease.

Furthermore, PHF-tau disrupts intracellular compartments that are essential for normal metabolism.

Cell culture studies show that the overexpression of tau causes a change in cell shape, retards cell growth and dramatically alters the distribution of various organelles transported by microtubule-dependent motor proteins.

In these studies, mitochondria fail to be transported to peripheral cell compartments and cluster in the vicinity of the microtubule-organizing center. Similarly, the endoplasmic reticulum no longer extends to the cell periphery and becomes less dense.

Moreover, transgenic mice that overexpress the four-repeat human tau protein isoform specifically in neurons develop axonal degeneration in the brain and spinal cord and have notable axonal dilations due to the accumulation of neurofilaments, mitochondria and other vesicular structures.