**2.15 5-Hydroxytryptamine 6 receptor**

The serotoninergic neurotransmitter system has been implicated in AD pathogenesis. The 5-hydroxytryptamine 6 receptor (5HTR6) is expressed in brain areas involved with cognitive processes and has been investigated as a possible therapeutic target in AD symptomatology. Besides, 5HTR6 may be added to currently approved "Food and Drug Administration" therapies: cholinesterase inhibitors and NMDA receptor antagonists since 5HTR6 controls the pyramidal neurons' migration during corticogenesis. In addition, 5HTR6 is a TOR signaling activator and seems to regulate GABAergic, glutamatergic, and cholinergic activity. Therefore, 5HTR6 is involved in cognition, anxiety, memory, affective state, among others [44]. Several kinds of research have been conducted with selective 5HTR6 antagonists. These antagonists act by modulating the glutamate and GABA levels, consequently increasing dopamine, ACh, and norepinephrine concentrations in

the brain, all compromised in AD. Besides, 5HTR6 agonists have also been shown to have pro-cognitive effects. Partial or inverse agonists may produce promising cognitive effects [44, 45]. Moreover, 5HTR6 gene variants can be a genetic risk factor for late-onset AD and 5HTR6 polymorphisms are possibly involved with AD susceptibility, such as the C267T polymorphism [44]. However, there are relatively few genetic studies investigating the association between AD and gene variants involved in the serotonergic system.

## **2.16 Cannabinoid receptors**

Evidence regarding the involvement of the endocannabinoid system (ECS) in the AD pathogenesis raised questions about the development of new therapeutic approaches for AD based on endocannabinoid regulation. The endocannabinoid system is composed of receptors, endogenous ligands, and enzymes, which are involved in AD pathogenesis [46]. Endocannabinoid system-directed drugs can exert beneficial effects on mood, as well as modulate neuroinflammation, synaptic plasticity, neurotoxicity, apoptosis, cell proliferation, cell differentiation, and oxidative stress [47, 48]. Moreover, cannabis tetrahydrocannabinol (THC) induces neurogenesis, removes Aβ peptides, and decreases neurofibrillary tangles. The hippocampus and microglia, key actors in dementia pathophysiology, express 1 and 2 cannabinoid receptors, respectively [49]. Type 2 cannabinoid receptor (CNR2) is overexpressed in activated microglia in different areas of the nervous system. Activated CNR2 has the potential to disrupt the AD process and treat the symptoms, reducing neurodegeneration, neuroinflammation, and improving spatial memory [50]. The role of the type 1 cannabinoid receptor (CNR1) is unclear. However, CNR1 can up-regulate anti-apoptotic proteins in rats [49].
