Research Article: Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease

Date Published: June 12, 2012

Publisher: Public Library of Science

Author(s): Claudio D’Addario, Andrea Di Francesco, Beatrice Arosio, Cristina Gussago, Bernardo Dell’Osso, Monica Bari, Daniela Galimberti, Elio Scarpini, A. Carlo Altamura, Daniela Mari, Mauro Maccarrone, Steven Estus. http://doi.org/10.1371/journal.pone.0039186

Abstract

Alzheimer disease (AD) is a progressive, degenerative and irreversible neurological disorder with few therapies available. In search for new potential targets, increasing evidence suggests a role for the endocannabinoid system (ECS) in the regulation of neurodegenerative processes.

We have studied the gene expression status and the epigenetic regulation of ECS components in peripheral blood mononuclear cells (PBMCs) of subjects with late-onset AD (LOAD) and age-matched controls (CT).

We found an increase in fatty acid amide hydrolase (faah) gene expression in LOAD subjects (2.30±0.48) when compared to CT (1.00±0.14; *p<0.05) and no changes in the mRNA levels of any other gene of ECS elements. Consistently, we also observed in LOAD subjects an increase in FAAH protein levels (CT: 0.75±0.04; LOAD: 1.11±0.15; *p<0.05) and activity (pmol/min per mg protein CT: 103.80±8.73; LOAD: 125.10±4.00; *p<0.05), as well as a reduction in DNA methylation at faah gene promoter (CT: 55.90±4.60%; LOAD: 41.20±4.90%; *p<0.05). Present findings suggest the involvement of FAAH in the pathogenesis of AD, highlighting the importance of epigenetic mechanisms in enzyme regulation; they also point to FAAH as a new potential biomarker for AD in easily accessible peripheral cells.

Partial Text

Alzheimer disease (AD) is the most frequent form of dementia in the elderly, affecting more than 25 million people worldwide; it is characterized by progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and cerebral cortex.

Gene expression of all major ECS elements in LOAD subjects and healthy controls was quantified and only FAAH mRNA was found to be altered by the disease (Figure 1). A significant increase of faah gene expression was observed in LOAD subjects compared to controls (LOAD: 2.30±0.48; CT: 1.00±0.14;* p<0.05) (Figure 2a). Also a decreased DNA methylation at faah gene was observed in LOAD patients compared to controls (CT: 55.90±4.60%, LOAD: 41.20±4.90%; * p<0.05) (Figure 2b). Consistently, a significant inverse correlation between gene expression and DNA methylation levels (Spearman r = −0.5326, * p<0.05) was evident in all samples that were large enough to allow both assays (Figure 2c). Many studies have recently documented a role for ECS in several neurological diseases, among which AD is a new promising area of research [27], [45]. Source: http://doi.org/10.1371/journal.pone.0039186