Short Article on Alzheimer's Disease: #4 Tau Phosphorylation

Tau is a major microtubule-associated protein primarily located in axons that contributes to the proper function of neurons. It associates with tubulin to promote their assembly into microtubules and also acts as a stabiliser for these structures. Upon mutations, post-translational modifications, oxidative stress or truncation, the binding of tau with microtubules becomes impaired and tau proteins dissociate and starts to self-aggregate into neurofibrillary tangles (NFT), one of the hallmarks of Alzheimer’s disease and other tauopathies.[1]

Hyperphosphorylation of Tau
Tau can undergo several post-translational modifications such as O-glycosylation, ubiquitination, SUMOylation, nitration, glycation, acetylation, conformational alteration, proteolytic cleavage and phosphorylation. [2]

Phosphorylation of tau proteins is normal and happens in healthy brains as the phosphorylation state of tau helps regulate its binding with tubulin. However, in Alzheimer’s disease, it happens multiple times and excessively. Over 50 phosphorylation sites involving Ser, Thr and Tyr residues have been identified or proposed with several hyperphosphorylated tau being identified in NFTs. [3] In particular, it has been shown that pathological phosphorylation of Tau at Ser396 or Ser404 decreases the binding activity of the Tau proteins to microtubules.[2]

Kinases involved in the hyperphosphorylation of Tau.
Phosphorylation of Tau involves the coordinated action of several kinases and phosphatase. In AD, amyloid beta not only disrupts communication between neurons, but also starts an immune response leading to inflammation. More specifically, amyloid beta causes the activation of p38 MAPK that results in the abnormal phosphorylation of tau proteins. Some tau kinases, which have been identified in AD include glycogen synthase kinase 3 beta (GSK3beta), cyclin dependant kinase CDK5, CaMKII and tyrosine kinases such as Src, Fyn and c-Abl, MARK. [4]

Phosphorylation of Ser422 inhibits the caspase cleavage of tau
Recent studies have reported that the proteolytic processing of tau by caspases, a family of cysteine proteases involved in apoptosis, generates truncated tau proteins that might play a role in the abnormal aggregation of tau. Indeed, it is known that tau protein contains several canonical sites for caspase cleavage and altered tau proteins including truncated tau proteins at the aspartic acid 421 site have been identified in tau tangles.[5,6] Also, in vitro experiments have demonstrated that caspase 3 could cleave the Asp421 site on tau with the resulting truncated tau proteins aggregating more readily than the full-length tau proteins.[1] However, this cleavage could be inhibited in vitro with tau proteins phosphorylated at the Ser422 site.[3,6]

Further reading:
Short Articles on Alzheimer’s Disease:
#1 Amyloid beta Formation
#2: Amyloid beta accumulation, imbalance of the production and clearance of Abeta
#3 Microglia
#5 Tau Aggregation and Propagation

References
[1] Structure and Pathology of Tau Protein in Alzheimer Disease, Kalarova M. et al, Int J Alzheimers Dis. 2012;2012:731526
[2] Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies? Alavi Naini SM et al, Oxid Med Cell Longev. 2015;2015:151979
[3] Ser422 phosphorylation blocks human Tau cleavage by caspase-3: Biochemical implications to Alzheimer’s Disease Sandhu P et al, Bioorganic & Medicinal Chemistry Letters, 2017; 27: 3, 642-652
[4] Oxidative stress and the amyloid beta peptide in Alzheimer's disease, Cheignon C et al, Redox Biol. 2018; 14:450-464.
[5] Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation, Kestoras ME et al, J Alzheimers Dis. 2016 Oct 18;54(4):1521-1538.
[6] Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo, Guillozet‐Bongaarts AL et al, J Neurochem. 2006 May;97(4):1005-14

Written by Magalie Dale
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