**4. Aβ structure**

The native conformation of Aβ is an unfolded protein. Aβ forms amyloid fibrils by folding from the native random-coil-rich state to α-helical-rich intermediate, and finally to a β-sheetrich amyloid monomer that self-assembles into the fibrils [24].

Another protein closely related to AD pathology is the tau protein. This is encoded in mapt gene, located on chromosome 17q21. Several tau isoforms are generated by alternative splicing, creating high and low isoforms. The human central nervous system expresses six low molec‐ ular weight isoform ranging from 352 to 441 amino acids [25].

Tau is a neuronal cytosolic protein whose function is to promote microtubules polymerization and stabilization. In addition, Tau has importance in maintaining an appropriate morphology of neurons and it appear to modulate axonal transport [26, 27].

Domains of Tau are defined on the basis of their microtubule interaction and their amino acid character. The C-terminal domain (assembly domain) binds microtubules while the Nterminal domain projects away from microtubule (projection domain). The overall amino acid tau composition is hydrophilic, consistent with its unfolded character; however, the Nterminal is predominantly acidic and the C-terminal roughly neutral, which is important for microtubule interaction. The middle region is a proline-rich domain which is targets of many proline-directed kinases and binding sites for proteins with SH3 domains [28]. Tau is highly regulated and is subject to multiple post-translational modifications. Phosphorylation is the most common tau post-translational modification described resulted from the equilibrium between the amount and activity of protein kinases and phosphatases.

Hyperphosphorylation of tau is not only associated with the disease, but is also employed by the neuron to downregulate its activity transiently and reversibly where required, for example during development, anesthesia, and hypothermia. It is the nonreversible nature of the abnormal hyperphosphorylation of tau in AD and other tauopathies that results in an involuntary slowing down of neuronal activity and a consequent chronic progressive neuro‐ degeneration [29]. Increased tau phosphorylation decreased its affinity for microtubules resulting in an abnormal increase in the levels of the free (unbound) Tau fraction; next small nonfibrillary tau deposits (normally referred to as "pretangles") are formed followed by structural rearrangement involving the formation of the characteristic pleated β-sheet struc‐ tures, which finally form the neurofibrillary tangles by self-assemble [26].
