# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 1 Introduction
MTs result from the head-to-tail polymerization of \(\alpha\)- and \(\beta\)-tubulin heterodimers [19], being always vibrating alternatively between growing and shrinking phases [20]. This dynamic nature of MTs results in the formation of several arrangements within cells. As MTs result from different isoforms of tubulin, their dynamism and their interaction with associated proteins (MAPs) regulates the morphology, stability, and their function in different cell types [21]. If this tuned process fails, AD or other neurodegenerative disorders will take place [22]. It has been concluded that stabilization of MTs may also potentially prevent AD progression. AD prevention also occurs by reducing hyperphosphorylation of \(\tau\)-protein, avoiding MTs dysfunction. As \(\tau\)-protein phosphorylation results from an equilibrium between \(\tau\)-kinase and phosphatase activities, the aggregation and the formation of NFTs is restrained by kinase inhibitors [23; 24; 25]. Thus, inhibition of these protein kinases [26] constitutes another strategy to combat AD. The most important protein kinase that is involved in \(\tau\)-phosphorylation is the glycogen synthase kinase-3 beta (GSK-3\(\beta\)) [10; 14]. AD development may also be avoided by inhibiting inflammatory response of microglial cells [27; 28]. When properly stimulated, microglia cells can transform themselves by modifying their shapes, releasing proinflammatory/neurotoxic factors, such as interleukin-1 (IL-1\(\beta\)), interleukin-6 (IL-6), tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), nitric oxide (NO) and reactive oxygen species (ROS) [29; 30; 31]. Accumulation of these proinflammatory/neurotoxic factors damages and causes degeneration of the nearby neurons. They release immune substances, increasing inflammatory neurotoxicity and causing irreversible neuroinflammationlammation [32; 33; 34]. Another potential therapeutic strategy to combat AD is, therefore, the use of inhibitors of microglia response. The decline of cognitive functions in AD patients is associated with the deficiency of the brain neurotransmitter acetylcholine (ACh). Upon action of the acetylcholinesterase enzyme (AChE), ACh breaks down giving acetate and choline, which is uptaken into the presynaptic neuron and carried out by choline carriers. The signal transduction at the neuromuscular junction finishes rapidly [35]. On the other hand, ACh binds to several receptors in the synaptic cleft. One of them, nicotinic ACh receptors (nAChRs) in the central nervous system (CNS), controls the liberation of other neurotransmitters which are involved in cognitive processes and memory [36; 37]. Inhibition of AChE prevents the hydrolysis of Ach, increasing its concentration and duration of action, which is clinically beneficial for AD patients. Thus, AChE inhibitors are widely used for AD treatment [36]. AD pathology can, therefore, progress through different pathways which can even be related. For example, AChE accelerates deposition of A\(\beta\) peptide [38] interacting also with A\(\beta\) deposits producing an AChE-A\(\beta\) complex, a very toxic substance, which in turn increases the intracellular calcium load and decreases mitochondrial membrane potential. The AChE-A\(\beta\) complex formation causes the neuronal cells death [39]. AChE also stimulates the protein kinase C (PKC) which inhibits GSK-3\(\beta\). Thus, the above mechanisms may work altogether through interaction between genetic, molecular and cellular events [40]. Several compounds have been identified to combat AD, and multitarget compounds represent an effective strategy for the treatment of this multifactorial disease [41; 42; 43]. For example, preventing the appearance of the A\(\beta\) plaques and cholinergic deficit are considered major contributing factors for AD. Thus, compounds which act simultaneously against BACE1 and AChE are multitarget compounds to combat AD.