The role of tau in neurodegeneration

Tania F Gendron,Leonard Petrucelli

doi:10.1186/1750-1326-4-13

Tania F Gendron, Leonard Petrucelli

Open Access

https://doi.org/10.1186/1750-1326-4-13

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Journal: Molecular Neurodegeneration	Publication Date: Jan 1, 2009
Citations: 394	License type: cc-by

Affiliation: Jacksonville College, Mayo Clinic

Abstract

Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, much effort has been directed towards determining how the aggregation of tau into fibrillar inclusions causes neuronal death. As evidence emerges that tau-mediated neuronal death can occur even in the absence of tangle formation, a growing number of studies are focusing on understanding how abnormalities in tau (e.g. aberrant phosphorylation, glycosylation or truncation) confer toxicity. Though data obtained from experimental models of tauopathies strongly support the involvement of pathologically modified tau and tau aggregates in neurodegeneration, the exact neurotoxic species remain unclear, as do the mechanism(s) by which they cause neuronal death. Nonetheless, it is believed that tau-mediated neurodegeneration is likely to result from a combination of toxic gains of function as well as from the loss of normal tau function. To truly appreciate the detrimental consequences of aberrant tau function, a better understanding of all functions carried out by tau, including but not limited to the role of tau in microtubule assembly and stabilization, is required. This review will summarize what is currently known regarding the involvement of tau in the initiation and development of neurodegeneration in tauopathies, and will also highlight some of the remaining questions in need of further investigation.

Highlights

The accumulation of proteinaceous aggregates is a pathological hallmark of many neurological diseases characterized by neuronal dysfunction and eventual cell death
The early axonal transport defects and synaptic damage could result from tau hyperphosphorylation and cytosolic accumulation whereas neurofibrillary tangles (NFT), which may initially be formed as a protective mechanism to sequester toxic tau moieties, could eventually contribute to neuronal death
Despite the growing body of evidence in strong support for the involvement of pathologically modified tau and tau aggregates in neurodegeneration, the exact neurotoxic tau species have not been definitively identified. Both toxic gains of function and the loss of normal tau functions are believed to play a role in inducing neuronal death but the mechanisms by which this occurs remain elusive

Summary

Introduction

The accumulation of proteinaceous aggregates is a pathological hallmark of many neurological diseases characterized by neuronal dysfunction and eventual cell death. Transgenic rats that overexpress truncated tau species (aa 151–391) in the brain and spinal cord develop neurofibrillary pathology [157], and cultured cortical neurons derived from these rats have fewer mitochondria in neuronal processes, display higher levels of reactive oxygen species and are more susceptible to oxidative stress compared to cultures from non-transgenic rats [159] Consistent with these findings, the expression of tau fragments cause cell death or render cells more sensitive to insults in various culture models [160,161,162,163]. Yoshiyama et al (2007), show that hippocampal synaptic loss is observed in transgenic mice overexpressing P301S htau (PS19 mice) before NFT formation [195] These mice develop early synaptic pathology; a prominent decrease in levels of the pre-synaptic proteins, synaptophysin and β-synuclein, is detected in the CA3 region of hippocampus by 3 months of age. These results suggest that β-amyloid triggers tau hyperphosphorylation, NFT formation and neurodegeneration

Concluding remarks

Komori T