Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood.
Alzheimer's disease and other tauopathies are characterized by the brain accumulation of hyperphosphorylated aggregated tau protein forming pathological inclusions.
Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases.
Accumulation of microtubule associated protein tau in the substantia nigra is associated with several tauopathies including progressive supranuclear palsy (PSP).
Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease.
This is a characteristic of tau protein in Alzheimer's disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson's disease, and huntingtin in Huntington disease.
The findings show that diverse clinical phenotypes relate most to the brain region degenerating rather than the type of pathology involved, that different regions on the MAPT gene and novel risk genes are associated with specific tau pathologies, that the 4-repeat glial tauopathies do not follow individual patterns of spreading as identified for neuronal pathologies, and that genetic and pathological data indicate that neuroinflammatory mechanisms are involved.
Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains.
In addition, Tau gene mutations, aberrant mRNA splicing and abnormal post-translational modifications, such as hyperphosphorylation, lead to formation of pathological, insoluble Tau aggregates that are a hallmark of neurodegenerative diseases, collectively known as tauopathies.
These results demonstrate that different combinations of FTDP-17 mutations and tau isoforms are functionally distinct and could have important implications for our understanding of disease and animal models of tauopathies.
The microtubule-associated protein tau is an attractive therapeutic target for the treatment of Alzheimer's disease and related tauopathies as its aggregation strongly correlates with disease progression and is considered a key mediator of neuronal toxicity.
Abnormal accumulation of tau protein is the main hallmark of tauopathies and is closely associated with neurodegeneration and cognitive impairment, whereas the advance in PET imaging provides a non-invasive detection of tau inclusions in the brain.
While questioning the potential role of Tau-DNA binding in the development of tauopathies, we have carried out a large-scale analysis of the interaction of Tau protein with the neuronal genome under physiological and heat stress conditions using the ChIP-on-chip technique that combines Chromatin ImmunoPrecipitation (ChIP) with DNA microarray (chip).
The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies.
Although the impact of MAPT (Tau) expression has been well documented for neuronal cells in the context of tauopathies and neurodegenerative diseases, the impact and role of Tau expression in cancer, and specifically cancers of neuronal origin, is in its infancy.