Endocannabinoid metabolism and Alzheimer's disease

Alzheimer ’s disease (AD) is the most common cause of dementia in the elderly. Unfortunately, there are no effective therapies currently available for prevention and treatment of AD. As it is clear now, the etiology of AD is multifactorial and complex. This means that development of AD is linked to multiple mechanisms or signaling pathways and that a single-target therapy for AD is likely insufficient to achieve therapeutic goals. Therefore, an ideal therapy for AD should be able to modify the disease through multiple signaling pathways. 2-Arach idonoy lg lycero l (2 -AG) i s an endogenous cannabinoid (endocannabinoid) d i s p l a y i n g a n t i i n f l a m m a t o r y a n d neuroprotective properties, whi le its metabolites are arachidonic acid (AA) and AA-derived prostaglandins and leukotrienes, which are proinflammatory and neurotoxic (Figure 1). The results from recent studies show that restraining 2-AG degradation reduces neuroinflammation, Aβ formation and tau phosphorylation, maintains the synaptic integrity, and improves long-term synaptic plasticity and cognitive function in mouse models of AD (Chen et al., 2012; Piro et al., 2012; Zhang et al., 2014; Zhang and Chen, 2018; Hashem et al., 2021). These beneficial effects produced by inhibition of 2-AG metabolism result likely from enhanced 2-AG signaling and concurrently decreased eicosanoid levels as 2-AG and eicosanoids mediate multiple signaling pathways (Figure 1), suggesting that limiting 2-AG metabolism in the brain would be an ideal therapy for AD. Endocannabinoids are naturally occurring lipid mediators involved in a variety of phys io log ica l , pharmaco log ica l , and pathological processes. Several lines of evidence indicate that endocannabinoids play an important role in maintaining brain homeostasis by modulating synaptic transmission and plastic ity, resolving n e u ro i n f l a m m at i o n , a n d p ro te c t i n g neurons from harmful insults (Chen, 2015). 2-AG is the most abundant endogenous endocannabinoid and a full agonist for cannabinoid receptor 1 and 2 (CB1R and CB2R). 2-AG is predominantly synthesized from diacylglycerol (DAG) by diacylglycerol l ipases (DAGLα and β) and hydrolyzed by monoacylglycerol lipase (MAGL), α/ β hydrolase domain-containing protein 6 and 12, and oxidatively metabolized by cyclooxygenase-2 when expression and activity of cyclooxygenase-2 are excessively elevated during inflammation (Figure 1). While 2-AG is degraded by several enzymes, it has been estimated that 85% of 2-AG in the brain is hydrolyzed by MAGL (Blankman et al., 2007), indicating the important role of MAGL in control of 2-AG levels in the brain. Recent studies provided new insights into synthesis and metabolism of 2-AG in the brain. It has been revealed that 2-AG in neurons and astrocytes is synthesized primarily through DAGLα, while it is formed in microglial cells through DAGLβ (Viader et al., 2015; Viader et al., 2016). On the other hand, MAGL is the primary enzyme hydrolyzing 2-AG in neurons and astrocytes, whereas α/β hydrolase domain-containing Chu Chen protein 12 is the major enzyme degrading 2-AG in microglial cells (Viader et al., 2016). This is further supported by the fact that there are no differences in the 2-AG levels between normal control mice and microglial MAGL knockout mice (Viader et al., 2015). In addition, the amount of 2-AG-generated in microglial cell only contributes a small proportion of 2-AG to the 2-AG pool in the brain (Viader et al., 2015). These results suggest that synthesis and degradation of 2-AG in the brain are cell type-specific.