Tau-mediated neurodegeneration in Alzheimer's disease and related disorders

Top Cited Papers
Publisher Website
Google Scholar
Abstract
This Review summarizes our current understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease and related disorders. It is believed that tau-mediated neurodegeneration might result from a combination of a loss of normal tau function (primarily the microtubule (MT)-stabilizing function of tau) with gains of pathological functions of hyperphosphorylated tau, and the filaments formed thereof. The primary function of tau is to stabilize the MTs. Under physiological conditions tau is in a tightly regulated dynamic equilibrium both on and off the MTs. This equilibrium, which is post-translationally regulated primarily by the phosphorylation state of tau, is thought to have a central role in maintaining effective axonal transport. Under pathological conditions, an excessive disengagement of tau from the MTs takes place. This abnormal disengagement is likely to cause axonal transport defects. Furthermore, the increased cytosolic concentration of unbound tau renders the tau more likely to undergo misfolding and aggregation. The aggregation of tau, leading to the formation of neurofibrillary tangles (NFTs), is likely to be associated with toxic gains-of-function. For example, NFTs may contribute to disease progression by further sequestering functional tau, thereby amplifying the loss of normal tau function. At the same time, relatively large NFTs may represent a direct physical obstacle to vesicles and other cargoes moving along the axons. Direct causes of the pathological disengagement of tau from the MTs include tau gene mutations and an imbalance between tau kinases and phosphatases. Other pathological events, such as Aβ-mediated neurotoxicity, oxidative stress and inflammation, may also be able to initiate or contribute directly or indirectly to tau mediated neurodegeneration; however, their precise positioning in the cascade of events that leads to neuronal loss remains unclear. A schematic overview of the various tau-directed therapeutic approaches currently under investigation is provided, along with an overview of the different transgenic mouse models that are available.