Progressive accumulation of hyperphosphorylated microtubule associated protein tau into neurofibrillary tangles and neuropil threads may be a typical feature of several neurodegenerative tauopathies, which includes Alzheimer disease , Choose illness, progressive supranuclear palsy, and frontotemporal dementias . Tau pathology has also been documented in men and women who suffered from a single serious traumatic brain injury or many mild, concussive injuries. Particularly, acute axonal accumulations of total and phospho tau have already been documented inside of hours to weeks , whereas NFTs have already been detected years following single significant TBI in humans . Additionally, NFT pathology is widespread in patients with lifetime histories of several concussive injuries . Tau pathologies in AD and TBI share very similar immunohistochemical and biochemical functions .
In both conditions, somatodendritic tau immunoreactivity is prominent; on the other hand, tau immunoreactive neurites observed in TBI have already been suggested to have an axonal origin, which may well be distinct in the threadlike varieties in AD recommended to get dendritic in origin . On top of that, the anatomical distribution of NFTs could possibly be different following TBI than is usually observed in AD . So, get more information the mechanisms top rated to tau hyperphosphorylation in TBI may differ from those in AD. The physiological perform of tau is to stabilize microtubules . Tau binding to MTs is regulated by serine threonine phosphorylation. Abnormally phosphorylated tau has decreased MT binding, which effects in MT destabilization. This in turn may compromise usual cytoskeletal function, eventually primary to axonal and neuronal degeneration . This is actually the basis to the hypothesis that tau hyperphosphorylation leads to neurodegeneration in tauopathies.
Identification of numerous mutations inside the tau gene, which induce frontotemporal dementia with selleck description parkinsonism linked to chromosome 17 and result in tau hyperphosphorylation, supports this hypothesis . Findings from experimental models during which human mutant tau is expressed present even more assistance for this hypothesis. In these versions, hyperphosphorylation of tau usually precedes axonopathy and degeneration . Consequently, targeting tau both by lowering its phosphorylation state or aggregation continues to be a emphasis of preclinical therapeutic improvement for AD and connected dementias . Two leading mechanisms proposed to underlie tau hyperphosphorylation are aberrant activation of kinases and downregulation of protein phosphatases.
Cyclin dependent kinase five and its co activator p25 , glycogen synthase kinase 3 , and protein phosphatase 2A are already implicated in hyperphosphorylation of tau in vivo. Other individuals such as protein kinase A , extracellular signal regulated kinase one 2 , and c Jun N terminal kinase have only been shown to manage tau phosphorylation in vitro.