Natural cannabinoids against Alzheimer’s disease: a role in glutamatergic regulation

[eng] Alzheimer's disease (AD), characterized by the loss of memory and other cognitive abilities, is the predominant form of dementia. Given the impact it has on individuals, affected families and health systems, it is considered a serious problem globally. Current treatments for this disease only minimally reduce the progression of cognitive and psychiatric symptoms, without offering a cure, which is why numerous alternative therapeutic strategies are currently being studied. In this sense, animal models are a valuable tool to understand the pathophysiological mechanisms that characterize the disease and identify suitable targets. During the development of this doctoral thesis, the APP/PS1 mouse has been used as an animal model of AD to study one of the mechanisms involved in the early stages of the disease: dysregulation of the glutamatergic system. It is characterized by an excess of the excitatory neurotransmitter glutamate, which causes excitotoxicity and neuronal damage. The endocannabinoid system (ECS) is a neuromodulatory system that is involved in numerous physiological functions, including glutamatergic transmission, which could be of interest in the context of neurodegenerative diseases such as AD. For this reason, there is a growing interest in the study of the therapeutic potential of natural cannabinoids (substances obtained from the Cannabis sativa plant) in AD and other neurodegenerative diseases, especially with regard to the combination of the two most abundant, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). The hypothesis of this doctoral thesis is that the combination of Δ9-THC and CBD is capable of regulating aberrant glutamatergic activity in a model of AD, thus contributing to the efficacy of this treatment as a therapy against this disease. In this context and based on previous evidence, the adenosine A2A receptor (A2AR) could contribute to the effects of Δ9-THC and CBD. To validate the working hypothesis, the following objectives were proposed: 1) To characterize the dysregulation of the glutamatergic system in the hippocampus of the APP/PS1 mouse, used as a model of AD. 2) To explore the effects of Δ9-THC and CBD on the alterations of glutamatergic activity observed in the hippocampus of APP/PS1 mice. 3) To evaluate the role of A2AR in the effects of Δ9-THC and CBD.