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).
Aguirre-Rueda, D., Guerra-Ojeda, S., Aldasoro, M., Iradi, A., Obrador, E., Mauricio, M.D., Vila, J.M., Marchio, P., and Valles, S.L. (2015). WIN 55,212-2, Agonist of cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture. PloS One 10, e0122843.
Ahmad, R., Postnov, A., Bormans, G., Versijpt, J., Vandenbulcke, M., and Van Laere, K. (2016). Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging 43, 2219–2227.
Altamura, C., Ventriglia, M., Martini, M.G., Montesano, D., Errante, Y., Piscitelli, F., Scrascia, F., Quattrocchi, C., Palazzo, P., Seccia, S., et al. (2015). Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer’s Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline. J. Alzheimers Dis. JAD.
Aso, E., and Ferrer, I. (2014). cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front. Pharmacol. 5, 37.
Aso, E., Andrés-Benito, P., Carmona, M., Maldonado, R., and Ferrer, I. (2016a). cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer’s Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine. J. Alzheimers Dis. JAD.
Aso, E., Andrés-Benito, P., and Ferrer, I. (2016b). Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model. J. Alzheimers Dis. JAD.
Bilkei-Gorzo, A., Albayram, O., Draffehn, A., Michel, K., Piyanova, A., Oppenheimer, H., Dvir-Ginzberg, M., Rácz, I., Ulas, T., Imbeault, S., et al. (2017). A chronic low dose of Δ(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat. Med.
Cao, C., Li, Y., Liu, H., Bai, G., Mayl, J., Lin, X., Sutherland, K., Nabar, N., and Cai, J. (2014). The Potential Therapeutic Effects of THC on Alzheimer’s Disease. J. Alzheimers Dis. JAD 42, 973–984.
de Ceballos, M.L., and Köfalvi, A. (2017). Boosting brain glucose metabolism to fight neurodegeneration? Oncotarget 8, 14273–14274.
Currais, A., Quehenberger, O., M Armando, A., Daugherty, D., Maher, P., and Schubert, D. (2016). Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. NPJ Aging Mech. Dis. 2, 16012.
Esposito, G., Scuderi, C., Valenza, M., Togna, G.I., Latina, V., De Filippis, D., Cipriano, M., Carratù, M.R., Iuvone, T., and Steardo, L. (2011). Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PloS One 6, e28668.
Hill, M.N., Titterness, A.K., Morrish, A.C., Carrier, E.J., Lee, T.T.-Y., Gil-Mohapel, J., Gorzalka, B.B., Hillard, C.J., and Christie, B.R. (2010). Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20, 513–523.
Köfalvi, A., Lemos, C., Martín-Moreno, A.M., Pinheiro, B.S., García-García, L., Pozo, M.A., Valério-Fernandes, Â., Beleza, R.O., Agostinho, P., Rodrigues, R.J., et al. (2016). Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer’s disease. Neuropharmacology.
Koppel, J., Vingtdeux, V., Marambaud, P., d’Abramo, C., Jimenez, H., Stauber, M., Friedman, R., and Davies, P. (2014). CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer’s disease. Mol. Med. Camb. Mass 20, 29–36.
Libro, R., Diomede, F., Scionti, D., Piattelli, A., Grassi, G., Pollastro, F., Bramanti, P., Mazzon, E., and Trubiani, O. (2016). Cannabidiol Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells. Int. J. Mol. Sci. 18.
Lou, J., Teng, Z., Zhang, L., Yang, J., Ma, L., Wang, F., Tian, X., An, R., Yang, M., Zhang, Q., et al. (2017). β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the cannabinoid Receptor Type 2 -Mediated Pathway. Front. Pharmacol. 8, 2.
Marchalant, Y., Cerbai, F., Brothers, H.M., and Wenk, G.L. (2008). cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol. Aging 29, 1894–1901.
Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G., Cuadrado, A., and de Ceballos, M.L. (2012). Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflammation 9, 8.
Navarro-Dorado, J., Villalba, N., Prieto, D., Brera, B., Martín-Moreno, A.M., Tejerina, T., and de Ceballos, M.L. (2016). Vascular Dysfunction in a Transgenic Model of Alzheimer’s Disease: Effects of CB1R and CB2R cannabinoid Agonists. Front. Neurosci. 10, 422.
Pascual, A.C., Martín-Moreno, A.M., Giusto, N.M., de Ceballos, M.L., and Pasquaré, S.J. (2014). Normal aging in rats and pathological aging in human Alzheimer’s disease decrease FAAH activity: Modulation by cannabinoid agonists. Exp. Gerontol. 60, 92–99.
Pascual, A.C., Gaveglio, V.L., Giusto, N.M., and Pasquaré, S.J. (2017). 2-arachidonoylglycerol metabolism is differently modulated by oligomeric and fibrillar conformations of amyloid beta in synaptic terminals. Neuroscience.
Ramírez, B.G., Blázquez, C., Gómez del Pulgar, T., Guzmán, M., and de Ceballos, M.L. (2005). Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. Off. J. Soc. Neurosci. 25, 1904–1913.
Sarne, Y., Toledano, R., Rachmany, L., Sasson, E., and Doron, R. (2017). Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. Neurobiol. Aging 61, 177–186.
Scuderi, C., Esposito, G., Blasio, A., Valenza, M., Arietti, P., Steardo, L., Carnuccio, R., De Filippis, D., Petrosino, S., Iuvone, T., et al. (2011). Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide. J. Cell. Mol. Med. 15, 2664–2674.
Tolón, R.M., Núñez, E., Pazos, M.R., Benito, C., Castillo, A.I., Martínez-Orgado, J.A., and Romero, J. (2009). The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res. 1283, 148–154.
Vázquez, C., Tolón, R.M., Grande, M.T., Caraza, M., Moreno, M., Koester, E.C., Villaescusa, B., Ruiz-Valdepeñas, L., Fernández-Sánchez, F.J., Cravatt, B.F., et al. (2015). endocannabinoid regulation of amyloid-induced neuroinflammation. Neurobiol. Aging.
Wang, L., Liu, B.-J., Cao, Y., Xu, W.-Q., Sun, D.-S., Li, M.-Z., Shi, F.-X., Li, M., Tian, Q., Wang, J.-Z., et al. (2017). Deletion of Type-2 cannabinoid Receptor Induces Alzheimer’s Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3β Pathway. Mol. Neurobiol.
Wu, J., Hocevar, M., Foss, J.F., Bihua Bie, B., and Naguib, M. (2017). Activation of CB2 receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer’s disease. Eur. J. Pharmacol.
Zhang, J., and Chen, C. (2017). Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors. Mol. Neurobiol.