Question

How does arachidonic acid induce fibrillation of Tau?

Answer 1

Tau protein is a microtubule associated protein that is concentrated in the neuronal axons in a weakly phosphorylated state. Tau is involved in microtubule assembly and axonal transport of neurotransmitters. Tau assembles microtubules via binding of its C terminal domain with α and β-tubulin. Hyperphosphorylation of tau occurs in Alzheimer’s disease due to increased kinase acitivity or reduction in phosphatase activity. This hyperphosphorylated tau accumulates in dendrites and neuronal cell bodies. Hyperphosphorylated tau binds to other tau proteins rather than microtubules to form tau oligomers. Tau oligomer form helical filaments that subsequently form neurofibrillary tangles.

Arachidonic acid in its free forms can induce tau polymerization in vitro. Tau polymers activate microglial cells. Arachidonic acid is an polyunsaturated fatty acid present in brain. They are attached to the central carbon of the glycerol backbone of the phospholipids in the cell membrane. Arachidonic acid induces tau polymerization by a ligand dependent nucleation-elongation mechanism. Two of the enzymes that phosphorylate tau, PKNα and PKCξ are activated by their binding to arachidonic acid. PKNα is a 3 PKC-homologous serine/protein kinases (PKN), that accumulates in neurofibrillary tangles in Alzheimer’s patient. PKCξ targets leucine-rich repeat kinase 2 [LRRK2] to induce tau phosphorylation Lipogenase derivatives of arachidonic acid also induce tau phosphorylation..