Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau phosphorylation in wild-type and MAPT transgenic mice.

In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice.

Electrical high frequency stimulation of the nucleus accumbens shell does not modulate depressive-like behavior in rats.

Deep brain stimulation (DBS) is an effective tool for treatment-resistant depression, though it is still unclear which brain area to target in order to get robust results. While research suggests that the nucleus accumbens (NAc) plays an important role in depression, studies using NAc DBS to improve depressive behavior have not been able to fully explain underlying molecular mechanisms. We therefore used unilateral high frequency stimulation of the NAc shell in rats to verify its effectiveness in treating depression and study involved neurotransmitter systems. Animals underwent social isolation and food deprivation to induce depressive-like symptoms, and performed the forced swim test (FST) to see possible changes in depressive behavior due to NAc shell stimulation. Neurotransmitter levels were measured using in-vivo microdialysis to detect DBS-induced changes. Non-treated control rats showed no significant difference between swimming and floating during FST, verifying that our depression model induced depressive-like symptoms in rats. Furthermore, stimulated and sham-operated animals showed a significant increase in mobility during FST compared to control rats, suggesting an improvement of depressive-like symptoms. However, stimulated rats did not differ from sham-operated rats in their behavior during FST, nor did neurotransmitter levels significantly changed in stimulated rats compared to control rats. Our data suggest that NAc shell stimulation did not alter depressive behavior in rats and had no effects on the molecular level. However, depressive behavior was positively altered when stimulation electrode and microdialysis probe were inserted simultaneously into the NAc shell, causing significant tissue damage and therefore possibly altering the glutamatergic system.