Table 2.

Therapeutic targets of AD and their role in AD pathogenesis.

Therapeutic Target	Role in AD Pathogenesis	References
AChE	To hydrolyze ACh in synapses To form complexes with Aβ peptide, modify its conformation and promote its aggregation to form β-amyloid plaques	[25,28]
BuChE	To hydrolyze ACh and the concentration of BuChE is found to be increased in advanced AD	[71]
BACE-1	To work with γ-secretase to degrade APP and generate Aβ peptide	[15]
GSK-3β	To hyperphosphorylate Tau proteins, separate them from microtubules and aggregate them into insoluble NFTs To regulate γ-secretase to induce Aβ peptide formation	[16,19]
MAO: MAO-A and MAO-B	To catalyze oxidative deamination To increase production of hydrogen peroxide and ROS To cause oxidative injuries and a toxic environment of neurodegeneration	[72,73]
Metal ions	Excess metals in brain cause peptide aggregation and oxidative stress Dysregulation of Cu2+ and Zn2+ induces generation of toxic Aβ oligomers by binding to Aβ peptides
NMDA receptor	To modify major forms of synaptic plasticity that contribute to learning and memory, and to consolidate short-term memory into long term memory Its overstimulation by excess glutamate will cause excitotoxicity and cell death Appropriate inhibition will improve the condition of AD patients	[23,24]
5-HT receptor (serotonergic receptor)	5-HT1A receptor has a therapeutic role in depressive disorder; the agonist and antagonist could be potential therapies for AD 5-HT4 receptor partial agonist can enhance ACh release, promote non-amyloidogenic cleavage of APP, form neurotrophic human sAPP-α fragments and decrease Aβ secretion 5-HT6 receptor antagonist can alleviate AD symptoms by enhancing cholinergic neurotransmission	[74,75]
SERT	To transport serotonin from the synaptic cleft back to the presynaptic neuron To terminate serotonergic signaling through reuptake of neurotransmitters into presynaptic neuron	[76]
PDE	To hydrolyze and degrade secondary messengers including cAMP and cGMP Regulators of signal transduction in neuroplasticity and neuroprotection Its inhibition can decrease the GSK-3β activity and level of hyperphosphorylated tau proteins	[77,78]
CB2 receptor	Activation of CB2 receptor reduces production of pro-inflammatory molecules by modulating migration of macrophages	[79,80,81]
H3 receptor	Activation of H3 receptor (autoreceptor and heteroreceptor) provides negative feedback in the histaminergic system Its activation also inhibits release of other neurotransmitters	[82,83]
AGEs	Glycation of tau proteins, leading to formation of paired helical filaments Glycation of Aβ peptide, resulting in increase in self-aggregation To provoke generation of reactive oxygen species	[84,85]
FAHH	To degrade endocannabinoid mediator, anandamide; endocannabinoid system in CNS plays a crucial role in learning and memory Its expression is elevated during inflammation and neurodegenerative processes	[86]
Nrf2	One of the components in Kelch-like ECH-associated protein 1 (Keap1)- nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway involved in defense mechanisms of cells against oxidative stress To initiate transcription of antioxidant genes and phase II detoxifying genes Its activation inhibits the induction of pro-inflammatory cytokines and enzymes	[87,88]
COX-2	To convert arachidonic acid to prostaglandins, which are the important inflammatory mediators; the level of prostaglandins is found increased in the frontal cortex of AD patients Its expression is remarkably elevated in the brains of AD patients	[89]
5-LOX	Its expression is found elevated in AD brains which has been associated with increased Aβ production and tau phosphorylation Its inhibition can reduce the amyloid and tau pathology as well as to improve cognitive impairment Association with oxidative stress in AD patients	[90]
SHIP2	Its inhibition reduces hyperphosphorylation of tau protein by FcγRII receptor	[91,92]