engleski

PROTEOLYSIS AND FRAGMENTATION OF TAU PROTEIN: TRANS-SYNAPTIC SPREADING OF NEUROFIBRILLARY DEGENERATION IN ALZHEIMER’S DISEASE AND OTHER SPORADIC TAUOPATHIES

There is no effective treatment for Alzheimer’s disease (AD). In the past 10 years many drugs discovery attempts based on the amyloid cascade hypothesis were not successful in meeting their prospective endpoints in late stage clinical studies, so alternate targets for AD have gained more attention. Tau protein has become an increasingly important therapeutic target based on advances in understanding its role in AD pathogenesis. Although since the 1980s it was known that neurofibrillary lesions (neurofibrillary tangles, NFT, neuropil threads, NT, and neuritic plaques, NP) are composed of hyperphosphorylated and aggregated forms of the microtubule-associated protein tau, it was thought that tau accumulation was primarily a consequence of the initial pathological changes induced by amyloid beta (Aβ) protein and not a major contributing factor for the initiation and progression of AD. In other words, NFT were considered indicators of cell death, particularly given that since 1995 their progression and number have been consistently shown to correlate well with severity of dementia in AD, while Aβ plaque deposition does not. Besides the fact that NFT-bearing neurons in AD brain have abnormal quantity and/or distribution of synaptic proteins, tau toxicity is also supported by findings from neuronal cell models where tau aggregation also leads to activation of caspase cascades and abortive apoptosis (abortosis) cell death. In AD, it is thought that the balance of tau kinase and phosphatase activity is shifted, creating a highly phosphorylated species of tau. This increases the fraction of unbound tau, which is no longer attached to microtubules, allowing for monomeric hyperphosphorylated tau to bind one another to produce oligomers. These oligomers are abnormally sorted from the axonal to somatodendritic compartment, where they undergo further phosphorylation and conformational change and take on a β-sheet structure that is considered insoluble. Fusion of these oligomeric species leads to the formation of paired helical filaments (PHF), the primary constituent of NFT. Compelling evidence that tau malfunction or dysregulation alone can be sufficient to cause neurodegeneration came in 1998 from the identification of mutations in the TAU gene on chromosome 17 that cause frontotemporal dementia with parkinsonism (FTDP-17), making cytoskeletal abnormalities a central player in neurodegeneration in AD. More specifically, abnormal phosphorylation, aggregation, and proteolysis of the tau protein (in a socalled “pre-tangle” stage of neurofibrillary degeneration) have been neuropathologically documented to be an early and pivotal event in the pathogenesis of AD, but also other sporadic tauopathies, such as argyrophilic grain disease and progressive supranuclear palsy. Hyperphosphorylation interferes with the normal function of tau by abrogating its ability to stabilize and promote the assembly of microtubules. It is sufficient to induce loss of tau function as dephosphorylation of pathological tau proteins by phosphatases restores its microtubule- stabilizing activity in vitro. However, which variety of tau is the most toxic one (aggregated misfolded/fibrillar, soluble hyperphosphorylated/mislocalized or both) and whether that toxicity represents a gain or loss of function continues to be debated. As there is little direct evidence that tau fibrils themselves are toxic, increasing number of investigators favor the hypothesis that soluble forms of tau are more toxic to neuronal (mitochondrial trafficking, calcium regulation, caspase activation) and synaptic function (electrophysiological deficits, membrane disruptions and dendritic spine loss), and ultimately contribute to synaptic and neuronal degeneration (although in this view the formation of NFT may protect neurons acutely from the effects of toxic soluble tau ; Kopeikina et al., Transl. Neurosci, 2012). These and other observations added to a body of evidence that abnormal tau can be directly involved in spreading of AD pathology to neighbouring neurons. However, direct evidence for molecular mechanisms supporting this hierarchical progression has remained elusive. The most recent data obtained in the past three years indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated TAU transgenic mice (Iba et al., J. Neurosci., 2013), and that tau aggregates can be transferred from cell to cell in vitro (Guo et al., FEBS Lett., 2013) and in vivo (de Calignon et al., Neuron, 2012 ; Liu et al., PLoS One, 2012). These new findings suggest an attractive “new” target for development of disease modifying therapeutics for AD as well as for other tauopathies.

Tau protein; proteolysis; neurofibrillary degeneration

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