There is controversy about CB1 expression in AD but CB2 is significantly increased in AD patients, probably due to microglial activation around senile plaques (reviewed in: Aso and Ferrer, 2014).
Interestingly AD patients do show lower CB2 binding in PET studies (Ahmad et al., 2016).
In aged rats stimulation of CB1 reduces microglial activation and improves memory (Marchalant et al., 2008).
Vice versa, in the 5xFAD mouse model of AD CB1 blockade exacerbated neuroinflammation (Vázquez et al., 2015).
One therapeutic indication for CB2 is the stimulation of amyloid β plaque removal by macrophages. Similar effects were seen for 2AG and MAGL inhibitors. CB1 is not involved in plaque clearance.
In cell culture, CBD prevented hyper-phosphorylation of Tau/the formation of neurofibrillary tangles.
CBD may also have anti-inflammatory properties through activation of PPARγ. In addition, CBD stimulates neurogenesis and may therefore counteract neurodegeneration at multiple levels (Esposito et al., 2011).
Amyloid beta plaques, a hallmark of Alzheimer’s, induce neuroinflammation and astrogliosis. Endogenous PEA levels rise with astrogliosis. PEA, in turn, blocks pro-inflammatory cytokines through PPARα (Scuderi et al., 2011). This suggests that the PEA-PPARα interaction functions to curtail neuroinflammation and inhibit the progression of Alzheimer’s.
In cultured astrocytes, Aβ1-42 reduced cell viability and PPARγ expression and increased cellular inflammation and anti-oxidant capacity. Specific CB1 stimulation (with WIN55,212-2, a synthetic analog of THC) prevented all these effects and increased cellular viability (Aguirre-Rueda et al., 2015).
Anandamide (1 μM) or THC (50 nM) stimulate intraneuronal β amyloid removal and reduce neuroinflammation in cultured human neuronal cells (Currais et al., 2016).
Apart from stimulating plaque removal Anandamide also boosts neuronal glucose uptake in a CB2-dependent way (de Ceballos and Köfalvi, 2017; Köfalvi et al., 2016).
CBD, THC and AEA also have anti-oxidant properties, which may be neuroprotective in AD.
Exercise has been shown to be beneficial in neurological disorders like Alzheimer’s disease and depression. Exercise increases the production of new neurons in the hippocampus in rats. In addition, Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).
Alzheimer’s patients have higher serum levels of 2AG and PEA. In these patients, 2AG is positively correlated with cognitive performance suggesting therapeutic potential. PEA was inversely correlated with cognitive performance, underlining the differential characteristics of cannabinoids (Altamura et al., 2015).
2AG levels appear to correlate with the degree of β amyloid polymerization with reduced 2AG levels (due to reduced DAGL) in the presence of β amyloid oligomers and increased 2AG (DAGL) in the presence of β amyloid fibrils (Pascual et al., 2017).
Chronic treatment of aged mice with 3 mg/kg intraperitoneal THC restores hippocampal gene expression and cognitive function to the level of young adult mice in a CB1-dependent manner (Bilkei-Gorzo et al., 2017).
Interestingly even a single dose of 0.002 mg/kg THC can achieve the same effect on cognitive rejuvenation (Sarne et al., 2017).
In a similar way, activation of microglial CB2 in APP/PS1 transgenic AD-prone mice restores hippocampal plasticity and cognitive performance, presumably through the suppression of neuroinflammation (Wu et al., 2017). Interestingly, reduced β amyloid production and improved cognitive function was also observed in AD-prone mice lacking CB2 (Zhang and Chen, 2017). However, other studies with the same mice show the lack of CB2 exacerbates β amyloid production and plaque deposition without affecting memory impairment or tau hyperphosphorylation (Aso et al., 2016a; Koppel et al., 2014). Yet another study shows CB2 deletion does induce tau hyperphosphorylation and memory impairment (Wang et al., 2017). Although this controversy sheds doubt on the therapeutic value of CB2 manipulation in AD it does confirm the involvement of CB2 in β amyloid processing.
Treatment of APP/PS1 mice with 1:1 THC:CBD reduced memory impairment but not β amyloid deposition (Aso et al., 2016b).
Research in mesenchymal stem cells suggests that 5 μM CBD can downregulate AD-related genes (tau phosphorylase, secretase) in a TRPV1-dependent manner (Libro et al., 2016).
In patients with AD, FAAH levels are reduced in the frontal cortex suggesting Anandamide levels may be up in AD (Pascual et al., 2014).
In brain from AD patients CB1 and CB2 are present in senile plaques and CB1/2 nitration is increased. Stimulation of CB1/CB2 (WIN55,212-2) or CB2 (JWH-133) as well as synthetic THC (HU-210) prevents cognitive impairment and microglial activation (Ramírez et al., 2005) and stimulates plaque removal (Tolón et al., 2009).
In a similar way prolonged CB1/CB2 stimulation prevents β amyloid accumulation and neuroinflammation and improves cognitive performance in APP 2576 transgenic mice (Martín-Moreno et al., 2012).
In βAPP N2A cells THC dose-dependently lowered β amyloid levels (Cao et al., 2014).
APP transgenic mice show increased cerebral vasoconstriction which can be reverted by CB2 and/or CB1 stimulation (Navarro-Dorado et al., 2016).
In a rat model of vascular dementia caryophyllene (in a synthetic complex) attenuated learning deficits suggesting therapeutic potential (Lou et al., 2017).
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