Table 1.

Involvement of ECS in various pathological aspects of AD.

Mechanisms of AD Pathogenesis	Implications of the ECS in AD		Cannabinoid Receptor Ligands with Potential Benefits in Therapeutic Management of AD
	Target Components	Physiological Function	Disease Model and Species	Compound	BIOLOGICAL EFFECT
β-amyloid (Aβ) peptides →neurodegenerative cascade → neuronal cell death [35,75,79,80]	CB1R activation	hyperpolarization of the neuronal membrane modulating of neurotransmitter and cytokine release [79]	Rats intra-CA1 microinjection i.p. intra-NAc intra-mPFC	ACPA (agonist of CB1R)	cognitive impairments [52,81]
[35,75,79,80]	↑ CB1R density	neuroprotective and anti-inflammatory response [79]	Rats intra-CA1 microinjection intra-NAc intra-BLA	AM251 (antagonist of CB1R)	enhanced memory and learning processes [52,81]
			Rat hippocampus	CBD and Δ9-THC	↑ synthesis of tryptophan → improvement of the disease [82]
			In vitro Methods Molecular docking	Cannabinoids (CBD, CBD-DMH)	↓ of oxidative stress ↓ of TNF-α synergistic effect with AchE inhibitors → preventing Aβ formation improvement of circadian rhythm disturbances commonly seen in AD [79,83]
proteolytic cleavage of β-APP → formation of Aβ1-42 monomers → activation of astrocytes and microglia → release of inflammatory cytokines, kinases and nitric oxide → phosphorylation of tau proteins [84]	Endocannabinoids (2-AG) CB1R/CB2R activation	synthesized by microglia and astrocytes → suppress cytokine synthesis via CB1/CB2 receptors	Primary hippocampal neuron cell cultures from rat embryos	MAGL inhibitors (URB 602 andJZL 184)	↑ endogenous levels of 2-AG → ↓ of TUNEL-positive neurons anti-apoptotic effects mediated through CB1R [85]
(added space) GSK-3β promotes tau proteinhyperphosphorylation → formation of NFT → impairing the axonal transport → neuronal atrophy [75]		neuroprotective effects → targeting this pathway with key roles in AD pathogenesis	PC12 cells treated with Aβ	CBD AEA WIN 55,212–2	attenuation of tau hyperphosphorylation by inhibiting Gsk-3β [75]
increased COX-2 levels → involvement in neuroinflammation [86]		2-AG is substrate for COX-2 2-AG suppress elevation of hippocampal COX-2 expression		MAGL inhibitor (URB602) and nonselective MAGL inhibitor (ATFMK)	↑ 2-AG levels → suppresses the expression of COX-2 action mediated by CB1R [86]
tau pathology [87]	CB2R activation	role in memory processing its activation → vital for cognitive processes a depletion or disruption of these receptors in rodents →induces long-lasting memory deficits	Rats	AM630 (CB2R antagonist)	negative effects such as impaired memory [87]
			Rats → impaired memory by administration of okadaic acid	JWH-133 (CB2R agonist)	reduced spatial memory impairment reduced neuroinflammation and neurodegeneration [87]
formation of Aβ peptide aggregates in the brain [88] PPAR- γ involvment in disease management [89]	CB2R activation	involved in controlling Inflammation	Beta-amyloid challenged astrocytes	CBD ± PPAR- γ antagonist (MK886 or GW9662)	interacts with the PPAR-γ receptor → attenuate beta-amyloid (Aβ)-induced neuroinflammation promote neurogenesis in the hippocampus [89]
Aβ peptide-induced neurotoxicity, oxidative stress and inflammatory status	CB2R activation	enhances immune system response andautophagy pathway	Analyses of transcriptome of APP/PS1 mice hypocampus	CBD, chronic i.p. injection (30 days)	improvement of the neuroinflammation and oxidative stress level [90]
neuroinflammatory mechanism	CB2R activation	ameliorate the neuroinflammation and cognitive impairments of AD	APP/PS1 mice	JWH015	improvement of novel object recognition regulation in microglia-mediated neuroinflammation [92]
evidence that associates neutrophil-derived myeloperoxidase (MPO) in the pathogenesis of AD	CB1R activation		Murine model (male mice) induced with focal cerebral ischaemia	Δ9-THC and SR141716 (CB1-R antagonist)/ AM630 (CB2R antagonist)	CB1R antagonist inhibited the neuroprotective effect of Δ9-THC CB2R antagonist had no effect reduction of the size of cerebral infarction given by MCA affective, cognitive, sensory and somatic effects, neuroprotective properties [52,75]
		mechanism of inhibition of myeloperoxidase independent of the cannabinoid receptor		CBD	(added space) the neuroprotective effect CBD was not inhibited by both CB1R and CB2R antagonist → effects, independent of cannabinoid receptors inhibition of MPO activity in neutrophils →anti-inflammatory mechanism pre- and post-ischaemic neuroprotective effect [91]
β-amyloid (Aβ) plaques cause injuries in the pulvinar nucleus → disruption of thalamo-cortical circuits including disturbances in visual attention [93]	CB1R NAPE-PLD FAAH located in the thalamus - pulvinar nucleus (lateral, medial and inferior) - dorsal lateral geniculate nucleus	physiological connections withprefrontal cortex and amygdala [94,95,96,97]	Coronal brain sections from Vervet monkey		lesioning of pulvinar nucleus → disturbance in perception of distracting stimuli [98] modulation of visual and spatial perception and processing mechanisms plasticity phenomena involving subcortical visual pathways synchronization of neural activity [99] (added space)
			Patients with AD	Δ9-THC CBD	↓of the lateral pulvinar nucleus ofAD patients [98] regular consumtioninterferes with emotional face recognition [100]

Legend: CA1: dorsal hippocampus; BLA: basolateral amygdala; NAc: nucleus accumbens; PFC: prefrontal cortex; and CBD-DMH: cannabidiol dimethylheptyl; ↓: decrease; ↑ = increase.