Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease

Abstract

The pathogenesis of Alzheimer's disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in microglia and in immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated migroglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

“…Several studies demonstrated that eCBs act as immunomodulators by inhibiting cytokine and chemokine production and microglial cell activation [ 42 , 43 ]. To validate our experimental settings, we assessed Aβ 25–35 induced microglia activation, which was partially counteracted by URB597, evaluating both the immunofluorescence signal of Iba1-positive cells and the Iba1 protein level, supporting the efficacy of URB597 on FAAH activity in BV-2 cells [ 27 ].…”

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

“…The retrograde endocannabinoid signalling system is a lipid-based neuromodulatory system with important roles in the CNS including in physiological and neurodegenerative processes [94,95]. It has been associated to pathogenesis of PD as well as AD and ischemia [95][96][97] and suggested as a therapeutic target for treatment of a range of neurodegenerative disorders including AD, PD, HD, multiple sclerosis (MS), and ALS [98][99][100]. Putative roles for its regulation via post-translational deimination have not been previously identified and therefore bring a novel angle of modulation of endocannabinoid signalling pathways in neurodegeneration, including in early disease stages.…”

Current Aspects of the Endocannabinoid System and Targeted THC and CBD Phytocannabinoids as Potential Therapeutics for Parkinson’s and Alzheimer’s Diseases: a Review

“…The ECS and its components have been widely studied in search for therapeutics for PD and AD [62,63]. The coexpression of CB1R and GPR55 has shown a significant neuroprotection against parkinsonism-inducing MPP + toxin [64].…”