There has been no link identified between the level of CB1 and AD but CB2 levels are significantly increased in people with AD (reviewed in Aso and Ferrer, 2014).
In PET studies, lower binding for CB2 was observed in people with AD (Ahmad et al., 2016).
In aged rats, microglial activation was reduced by stimulation with CB1. Also, memory was improved by stimulation with CB1 (Marchalant et al., 2008).
In the transgenic mouse model of AD, inflammation was exacerbated through blocking CB1 (Vázquez et al., 2015).
CBD may exhibit anti-inflammatory activity via activation of pparγ. Furthermore, CBD may help promote neurogenesis and consequently counteract neurogenesis (Esposito et al., 2011).
It was shown that palmitoylethanolamide (PEA; endogenous fatty acid amide) exerts anti-inflammatory effects by counteracting Aβ-induced astrogliosis (Scuderi et al., 2011). This proposes that PEA may function as a potential therapeutic agent in AD.
Cell viability and anti-inflammatory response in cultured astrocytes were shown to be increased by WIN 55,212-2 (a synthetic cannabinoid). However, further studies are needed to evaluate the effect of cannabinoids in AD (Aguirre-Rueda et al., 2015).
In cultured human neuronal cells, anandamide (1 μM) or THC (50 nM) were shown to promote the removal of intraneuronal Aβ and exhibit anti-inflammatory activities (Currais et al., 2016).
Anandamide was also shown to play a role in increasing neuronal glucose uptake in a CB2-dependent way (de Ceballos and Köfalvi, 2017; Köfalvi et al., 2016).
CBD, THC, and AEA have been reported to exhibit antioxidant activities, which may be neuroprotective in AD.
Exercise has been found to be helpful for patients with AD and depression. In a study with rats, it was observed that exercise caused the formation of new neurons in the hippocampus. Furthermore, in the hippocampus (but not in the prefrontal cortex), anandamide levels (and to lesser degree 2AG levels) and CB1 receptor availability were elevated.
Blocking the endocannabinoid system can affect the formation of new neurons (i.e. prevent new neuron generation), proposing that cannabinoids are involved in this process (Hill et al., 2010).
Higher serum levels of 2AG and PEA were observed in patients with AD. In these patients, a positive correlation was found between cognitive performance and 2AG, proposing therapeutic potential. An inverse correlation was seen between cognitive performance and PEA, highlighting that cannabinoids possess different characteristics (Altamura et al., 2015)
In mice, THC was shown to restore hippocampal gene expression and cognitive function (Bilkei-Gorzo et al., 2017).
In mice, age-related cognitive impairments were reversed upon treatment with THC (Sarne et al., 2017).
In APP/PS1 transgenic AD-prone mice, hippocampal plasticity, and cognitive performance were restored by activation of microglial CB2 (Wu et al., 2017).
Interestingly, in AD-prone mice lacking CB2, cognitive function was shown to be improved. Also, in AD-prone mice lacking CB2, β amyloid production was reduced (Zhang and Chen, 2017).
However, other studies found that β amyloid production and plaque deposition exacerbated due to the lack of CB2. Memory impairment or tau hyperphosphorylation was not found to be affected (Aso et al., 2016a; Koppel et al., 2014).
Another study found that deletion of CB2 triggers tau hyperphosphorylation and memory impairment (Wang et al., 2017).
Although the therapeutic value of CB2 manipulation is questionable in AD it does confirm that CB2 is involved in β amyloid processing.
Memory impairment but not β amyloid deposition was reduced upon treatment with 1:1 THC:CBD in AβPP/PS1 mice (Aso et al., 2016b).
In one study it was found that genes associated with AD can be downregulated by 5 μM of CBD in a TRPV1-dependent manner (Libro et al., 2016).
In patients with AD, fatty acid amide hydrolase levels were shown to be decreased in the frontal cortex, proposing that anandamide levels could be elevated in patients with AD (Pascual et al., 2014).
In AD patients, CB1 and CB2 are found in senile plaques. Cognitive impairment and microglial activation can be prevented through stimulation of CB1/CB2 (WIN55,212-2) or CB2 (JWH-133) and synthetic THC (HU-210) (Ramírez et al., 2005, Tolón et al., 2009).
In Tg APP 2576 mice, prolonged oral administration of cannabinoids have been shown to reduce β-amyloid levels, neuroinflammation, and ameliorate cognitive performance (Martín-Moreno et al., 2012).
In N2a/AβPPswe cells, THC in a dose-dependent-manner reduced β amyloid levels, suggesting that THC may have a therapeutic potential in AD (Cao et al., 2014).