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Abstract
Growing evidence shows that the immune system is critically involved in Alzheimer’s disease (AD) pathogenesis and progression. The modulation and targeting of peripheral immune mechanisms are thus promising therapeutic or preventive strategies for AD. Given the critical involvement of the endocannabinoid (eCB) system in modulating immune functions, we investigated the potential role of the main elements of such a system, namely type-1 and type-2 cannabinoid receptors (CB1 and CB2), and fatty acid amide hydrolase (FAAH), in distinct immune cell populations of the peripheral blood of AD patients. We found that, compared to healthy controls, CB1 and CB2 expression was significantly lower in the B-lymphocytes of AD patients. Moreover, we found that CB2 was significantly lower and FAAH was significantly higher in monocytes of the same subjects. In contrast, T-lymphocytes and NK cells did not show any variation in any of these proteins. Of note, monocytic CB2 and FAAH levels significantly correlated with clinical scores. Furthermore, the pharmacological inactivation of FAAH in monocytes and monocyte-derived macrophages obtained from AD patients was able to modulate their immune responses, by reducing production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-12, and enhancing that of the anti-inflammatory cytokine IL-10. Furthermore, FAAH blockade skewed AD monocyte-derived macrophages towards a more anti-inflammatory and pro-resolving phenotype. Collectively, our findings highlight a central role of FAAH in regulating AD monocytes/macrophages that could be of value in developing novel monocyte-centered therapeutic approaches aimed at promoting a neuroprotective environment.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia among people over the age of 65, accounting for 50–60% of all cases
Such were compared using the non-parametrical Mann–Whitney U test, whereas differences immunophenotypic characterization revealed that the AD patients had similar percentages between multiple groups were compared by one-way ANOVA followed by the Tukey in all the innate and adaptive immune cell subsets compared to the healthy controls
Our observed increase in fatty acid amide hydrolase (FAAH) in the monocytes of AD patients corroborates previous findings that reported an increase in this enzyme due to an altered epigenetic regulation of its gene promoter in total peripheral blood mononuclear cells of late-onset AD patients [7], but extends those findings and identifies monocytes as the immune cell population mostly responsible for reducing the eCB tone in AD
Summary
Alzheimer’s disease (AD) is the most common form of dementia among people over the age of 65, accounting for 50–60% of all cases. Biomolecules 2021, 11, 502 pathogenesis and progression are restricted to the neuronal compartment, but they involve strong interactions with immunological mechanisms occurring both within the brain and at the periphery. In the sporadic form of AD, the accumulation of Aβ42 is likely due to its defective clearance by microglial cells [2,3]. Recent research has shown that systemic immune dysfunctions are critically associated with AD pathology. The latter includes changes in the distribution and activation of specific innate and adaptive immune cell populations, or their infiltration in the brain, further sustaining and exacerbating neuroinflammation (3). Modulation and targeting of immune mechanisms are considered promising therapeutic/preventive strategies for AD [4]
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