Alzheimer's disease (AD) is the most common form of dementia. Numerous experimental findings show that targeting the endocannabinoid system, a complex network of cellular receptors (i.e. CB1 and CB2, mainly) and signaling molecules (i.e. endocannabinoids) highly expressed in brain, offers a multi-faceted approach for treating AD. In this sense, previous results from our research group demonstrated that the combination of non-psychoactive doses of the natural cannabinoid compounds Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) reduces the cognitive decline in a mouse model of AD more efficiently that each compound by itself. Our current research interest is focused in elucidating the molecular mechanisms underlying these effects.
We have already demonstrated that CB1R, but not CB2R, plays a crucial role in the progression of AD, since its blockade drastically reduces the survival of APP/PS1 mice and accelerates their memory impairment. Moreover, we have observed that CB1R and A2AR exhibit a reciprocal antagonistic functional interaction at the pre-synaptic level in the hippocampus, which underlies some of the effects of Δ9-THC and CBD. Other evidence suggested that A2AR overexpression in AD brains contributes to the cognitive decline by increasing glutamate release. Thus, considering such findings, we hypothesize that Δ9-THC and CBD would modulate CB1R-A2AR interaction, resulting in an attenuation of the A2AR overactivity described in AD, which would reduce glutamate release from pre-synaptic terminals and ultimately lead to a reduction of cognitive impairment in AD. To challenge our hypothesis, we employ state-of-the-art molecular pharmacology techniques and in vivo experimental approaches. The overall aim of this project is to optimize a future multimodal therapy against AD based on these natural cannabinoids.
Additional reading:
Adenosine A 2A-Cannabinoid CB 1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ 9-Tetrahydrocannabinol-Induced Cognitive Impairment. (2019) Aso, E., Fernández-Dueñas, V., López-Cano, M., Taura, J., Watanabe, M., Ferrer, I., Luján, R. & Ciruela, F. Molecular Neurobiology 56(8), 5382-5391.
Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model. (2018) Aso, E., Andrés-Benito, P. & Ferrer, I. Biochemical Pharmacology 157, 210-216.
Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model. (2016) Aso, E., Andrés-Benito, P. & Ferrer, I. Journal of Alzheimer Disease 54(3), 903-912.
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. (2016) Aso, E., Andrés-Benito, P. Carmona, M., Maldonado, R. & Ferrer, I. Journal of Alzheimer Disease 51(2):489-500.
Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. (2015) Aso, E., Sánchez-Pla, A., Vegas-Lozan,o E., Maldonado, R. & Ferrer, I. Journal of Alzheimer Disease 43(3):977-91.