Various other pathological events, including Aβ-mediated toxicity, as well as oxidative stress and inflammation, may be able to trigger or contribute (independently or in combination) to an abnormal detachment of tau from the MTs [17–20]. For example, it has been suggested that oxidative stress could be responsible for detrimental covalent modifications of tau, which include the formation of intermolecular disulphide bridges and tyrosine nitration. Such modifications are likely to cause misfolding, hyperphosphorylation and aggregation, and thereby contribute to abnormal disengagement of tau from MTs, as well as to the formation of aggregates. Although oxidative stress is often regarded as an upstream event relative to tau pathology, recent studies have revealed that pathological tau may interfere with mitochondrial function and induce oxidative stress [21–23]. In addition, lifetime stress, endoplasmic reticulum stress and hypersecrete glucocorticoids exposure also influence tau hyperphosphorylation [24, 25].
Kinases of tau
Several lines of in vitro data have shown that many kinases are involved in phosphorylation of tau, though it is not yet clear if it is also physiologically or pathologically true in vivo. Nevertheless, cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase 3 (GSK3), the microtubule-affinity-regulating kinase (MARK) and extracellular signal-regulated kinase 2 (ERK2) have received particular attention as potential targets for disease-modifying therapies using inhibitory compounds [7, 26].
P35 and p39 proteins are expressed almost exclusively in postmitotic neurons and have been identified as CDK5 activators . Elevated cellular calcium levels trigger the calpain-mediated cleavages of p35 and p39 to form the more stable p25 and p29 fragments [28, 29]. Indeed, calpain activation, p25 accumulation and elevated CDK5 activity have all been observed directly in the AD brain [30, 31]. This has also been evident in the transgenic mice that overexpress human p25 that exhibit increased CDK5 activity, hyperphosphorylation of tau, neurofilament and cytoskeletal disturbances . Inducible transgenic mice overexpressing p25 in the postnatal forebrain also exhibit neuronal loss and caspase-3 activation, accompanied by hyperphosphorylation of endogenous tau, accumulation of aggregated tau, and the progressively developed neurofibrillary pathology . Together, these data suggest CDK5-p25 pathway is a crucial component of AD pathophysiology. Interestingly, mice overexpressing p35 as well as tau and CDK5 do not show increased tau phosphorylation, and the cdk5/p35 could not cause neurodegeneration in mouse brain, suggesting that cdk5/p35 might not be a major protein tau kinase .
Cdk5 modulates tau hyperphosphorylation via the inhibitory regulation of GSK3 . GSK3 has two isoforms, GSK3α and GSK3β. In transfected mammalian cells, GSK3α and GSK3β could contribute to the formation of PHF [36, 37]. Transgenic mice with elevated GSK3β expressions show increased tau phosphorylation and deficits in spatial learning . In newborn AD transgenic mouse models, knockdown of GSK3α and GSK3β reduces tau phosphorylation and tau misfolding, while the knockdown of GSK3α, but not GSK3β, leads to reduced senile plaques formation. These data demonstrate that GSK3β only modulates NFT formation, while GSK3α contributes to both senile plaques and NFT pathogenesis .
MARK phosphorylates tau on non-Ser/Thr-Pro sites and plays a crucial role in regulating tau’s function. MARK selectively phosphorylates a KXGS motif, which is presented in each MT-binding domain of tau. Overexpression of MARK promotes tau phosphorylation at KXGS motifs and disrupts the microtubule array in vivo . Although little is known so far about the upstream events that act through MARK to regulate tau phosphorylation, one recent study demonstrated that GSK3β is substantially responsible for phosphorylating Ser-262 of tau through activation of MARK2 .
ERK2 is highly expressed in neurons and plays an important role in regulating tau functions and tau phosphorylation. This kinase can promotes tau phosphorylation and hereby reduce the ability of tau in stabilizing microtubules .
Besides the roles either directly or indirectly in modulating tau phosphorylation, recent studies have revealed that the kinases mentioned above are also associated with APP cleavage. For instance, GSK3, especially GSK3α, involves in APP processing, and the production of Aβ peptides can be significantly reduced by interfering APP cleavage at the gamma-secretase step with lithium, a GSK3 inhibitor . Inhibition of GSK3α may thus offer a new approach to reduce the formation of both amyloid plaques and NFTs. CDK5-p25 can also modulate the production of Aβ by increasing APP phosphorylation at Thr668 .
Phosphatases of tau
It has been identified that a number of phosphatases, such as protein phosphatase (PP) 1, PP2A, PP2B and PP2C, could potentially drive the reverse and dephosphorylation of tau. Their activities were found to be decreased about 20-30% in AD brain .
PP2A is co-localized with tau and microtubules in the brain and is apparently the most active enzyme in dephosphorylation of tau. In AD brain, both the expression and activity of PP2A are decreased. Tau can be abnormally hyperphosphorylated if I1PP2A, a 249-amino acid long endogenous inhibitor of PP2A, is increased . One recent study reported that PP2A could be inactivated via phosphorylation of its catalytic subunit at Y307. This PP2A inactivation can be mediated by Aβ deposition or estrogen deficiency in the AD brain. Moreover, the inactivation of PP2A consequently compromise dephosphorylation of abnormally hyperphosphorylated tau, therefore lead to neurofibrillary tangle formation .