Effect of Docosahexaenoic Acid (DHA) at the Enteric Level in a Synucleinopathy Mouse Model

Abstract

The aggregation of alpha-synuclein protein (αSyn) is a hallmark of Parkinson’s disease (PD). Considerable evidence suggests that PD involves an early aggregation of αSyn in the enteric nervous system (ENS), spreading to the brain. While it has previously been reported that omega-3 polyunsaturated fatty acids (ω-3 PUFA) acts as neuroprotective agents in the brain in murine models of PD, their effect in the ENS remains undefined. Here, we studied the effect of dietary supplementation with docosahexaenoic acid (DHA, an ω-3 PUFA), on the ENS, with a particular focus on enteric dopaminergic (DAergic) neurons. Thy1-αSyn mice, which overexpress human αSyn, were fed ad libitum with a control diet, a low ω-3 PUFA diet or a diet supplemented with microencapsulated DHA and then compared with wild-type littermates. Our data indicate that Thy1-αSyn mice showed a lower density of enteric dopaminergic neurons compared with non-transgenic animals. This decrease was prevented by dietary DHA. Although we found that DHA reduced microgliosis in the striatum, we did not observe any evidence of peripheral inflammation. However, we showed that dietary intake of DHA promoted a build-up of ω-3 PUFA-derived endocannabinoid (eCB)-like mediators in plasma and an increase in glucagon-like peptide-1 (GLP-1) and the redox regulator, Nrf2 in the ENS. Taken together, our results suggest that DHA exerts neuroprotection of enteric DAergic neurons in the Thy1-αSyn mice, possibly through alterations in eCB-like mediators, GLP-1 and Nrf2.

Sex and Age Differences in a Progressive Synucleinopathy Mouse Model

“…Analyses of microgliosis also revealed that the increase in the inflammatory response with aging in male mice was significant only in the SNCA-OVX types. Our results are in accordance with a previously reported increase in microgliosis in a Thy1-αSyn mouse model [ 21 , 74 ]. These increases in gliosis in synucleinopathy models can be explained by the possible interaction of αSyn with astrocytes and microglia [ 75 ].…”

Esterification of Docosahexaenoic Acid Enhances Its Transport to the Brain and Its Potential Therapeutic Use in Brain Diseases

“…Omega-3 fatty acids, and particularly DHA, can interact with α-synuclein to prevent its detrimental oligomerization [ 72 , 73 , 74 ]. Another pathway of action of DHA is the modulation of dopamine-induced neurodegeneration [ 75 , 76 ] and the enhancement of anti-oxidative pathways [ 76 ].…”