Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time. The main clinical hallmarks of the disease (e.g., beta-amyloid plaques and neurofibrillary tangles) begin during preclinical AD when cognitive deficits are not yet apparent. Hence, a more profound understanding of AD pathogenesis is needed to develop new therapeutic strategies. In this context, the endocannabinoid (eCB) system and the gut microbiome are increasingly emerging as important players in maintaining the general homeostasis and the health status of the host. However, their interaction has come to light just recently with gut microbiota regulating the eCB tone at both receptor and enzyme levels in intestinal and adipose tissues. Importantly, eCB system and gut microbiome, have been suggested to play a role in AD in both animal and human studies. Therefore, the microbiome gut-brain axis and the eCB system are potential common denominators in the AD physiopathology. Hence, the aim of this review is to provide a general overview on the role of both the eCB system and the microbiome gut-brain axis in AD and to suggest possible mechanisms that underlie the potential interplay of these two systems.
Highlights
Alzheimer’s disease (AD) is a chronic age-related progressive neurodegenerative disorder accounting for ~80% of dementia globally
The aim of this review is to provide a general overview on the role of both the eCB system and the microbiome gut-brain axis in AD and to suggest possible mechanisms that underlie the potential interplay of these two systems
Deletion of MAG lipase (MAGL) in astrocytes attenuated LPS-induced neuroinflammation in mice and genetic MAGL inactivation in PS1/amyloid precursor protein (APP) AD model reduced prostaglandin production, Aβ levels and plaques [190,191]. This suggests that MAGL is a key modulator of gut microbiota composition, inflammation and amyloidosis and might be considered as a potential next-generation target whose deep investigation might provide new therapeutic strategy against AD etiology and its modifiable risk factors. Both the eCB system and the gut microbiota have individually emerged as molecular targets in the pathology of AD as they may counteract inflammatory, neurodegenerative and cognitive aspects of the disease, research on the complex interactions of these systems in AD is still missing
Summary
Alzheimer’s disease (AD) is a chronic age-related progressive neurodegenerative disorder accounting for ~80% of dementia globally. The full understanding of the disease pathogenesis and the identification of therapeutic strategies that may prevent or delay disease progression appear urgent [1] In this scenario, increasing interest has been focused on the gut microbiome and the endocannabinoid (eCB) system as emerging targets involved in the control of AD. The eCB system that is ubiquitously expressed throughout the gut, periphery and brain is well recognized to participate in almost all human physiological processes and to be involved in several pathological conditions [13,14,15,16] Studies performed in both AD-like animal models and patients suggested that eCB system alterations are associated with AD pathophysiology, and that its pharmacological modulation may have disease-modifying effects [17,18]. We discuss the potential connection between the eCB system and the gut-brain axis in AD
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