Alzheimer's disease (AD) is characterized by
dementia, cognitive disabilities, and
tauopathy. Tau is a
microtubule associated protein that helps maintain the neuronal network. While phosphorylation of
tau protein causes disruption of the microtubular network, dephosphorylation allows reconstitution of the microtubule network. Several
kinases, e.g., MARK, MAPK, and
protein kinase C, are known to hyperphosphorylate tau, leading to disruption of the microtubular network and formation of neurofibrillary tangles (NFTs), which are further glycosylated, glycated, and have
lipid peroxide adducts that impair the neuronal transport system and affect memory formation and retention. Moreover, intracerebral administration of
amyloid-β oligomers causes hyperphosphorylation of tau, but whether it is involved in the formation of NFTs is still unclear. Further,
amyloid burden activates
AMP-activated protein kinase that increases phosphorylation of tau at position Ser262/Ser356 and Ser396. Several
phosphatases are present at low levels in AD brains indicating that their down regulation results in abnormal hyperphosphorylation of tau. However, evidence strengthens a possible link between tau phosphorylation and
molecular chaperone mediated tau metabolism for the clearance of toxic tau accumulation and has a crucial role in
tauopathy. Furthermore, accumulation of phosphorylated
tau protein and the possibility of removing the toxic phosphorylated
tau protein from the milieu indicates that the chaperone interacts with phosphorylated tau and promotes its degradation. For instance, Hsp90 and cdc37 regulate tau stability and phosphorylation dynamics whereas Hsp27 is able to modulate neuronal plasticity, while 14-3-3 is involved in the interaction of tau with small HSPs. Hsp70
ATPase acts as a modulator in AD
therapeutics while Hsc70 rapidly engages tau after microtubular destabilization. Herein, we highlight the various causes of
tauopathy and HSP-E3
ligase mediated
therapeutics in AD.