**3. Aβ and tau**

Aβ isoforms are 39–43 amino acid peptides present as soluble Aβ<sup>40</sup> or insoluble Aβ42. In physiological condition, Aβ<sup>40</sup> represents more than 90% of Aβ while Aβ<sup>42</sup> levels are less than 5%. A possible function of Aβ under physiological conditions may be inhibiting γ-secretase activity to generate more Aβ in a negative feedback control mechanism [17]. However, under pathological conditions, Aβ42 which is found in high concentrations in AD patients is prone to aggregate lacking the ability to inhibit γ-secretase [18–20].

Aggregated Aβ peptides, either soluble oligomers or fibrils, could induce a cascade of cellular events such as apoptosis [21–24], oxidative injury [24–26], alterations in kinase or phosphatase activities [26–29], microglial activation [30–32], and mitochondrial dysfunction [33–35], which trigger neuronal death [36, 37].

The role of Aβ in AD pathogenesis has been extensively investigated by a large number of studies. However, only Aβ accumulation is not sufficient to induce AD pathology. AD pathogenesis requires tau protein accumulation and deposits [38, 39]. Some evidence supports the notion that Aβ deposition induces tau pathology by promoting the intra-neuronal formation of NFT which consist of hyper-phosphorylated tau proteins. However, whether Aβ directly interacts with tau aggregates is still under debate [40].

Tau has been identified 40 years ago as a microtubule-associated protein by Weingarten et al [41]. Tau is a highly soluble neuronal protein [42] mainly located in the axons, which promotes microtubule polymerization and stabilization [43]. There are six isoforms expressed in the central nervous system [44]. Under physiological conditions, tau plays an important role in the regulation of axonal transport, neuronal signaling pathways, DNA protection, and synaptic function [45–47]. During early stages of development, tau isoforms are highly phosphorylated [44], and it is hypothesized that fibrillary deposits of hyper-phosphorylated tau contribute to synaptic dysfunction in AD [48].
