Changes in dietary folate intake differentially affect oxidised lipid and mitochondrial DNA damage in various brain regions of rats in the absence/presence of intracerebroventricularly injected amyloid ß-peptide challenge.

Accumulating evidence suggests that changes in dietary folate intake may modulate the risks of Alzheimer's disease (AD) through as yet unknown mechanisms. The aims of the present study were to investigate how dietary folate affects the brain folate distribution, levels of oxidised lipid and DNA damage in the absence/presence of ß-amyloid(25-35) (Aß) peptide challenge, a pathogenic hallmark of AD. Male Wistar rats were assigned to diets with folic acid at 0 (folate deprivation; FD), 8 (moderate folate; MF) and 8 mg folic acid/kg diet+0·003 % in drinking-water (folate supplementation; FS) for 4 weeks. A single injection of Aß peptide (1 mg/ml) or the vehicle solution was intracerebroventricularly (icv) administrated to rats a week before killing. Brain folate, a marker of oxidative injury, and neuronal death were assayed. In the absence of an Aß injection, FD rats showed reduced folate levels, and increased 2-thiobarbituric acid-reactive substances and a mitochondrial (mt)DNA 4834 bp large deletion (mtDNA4834 deletion) in the hippocampus compared with the counterpart brains of control rats (P < 0·05). A single icv injection of Aß peptide potentiated lipid peroxidation in the medulla of FD rats, which was ameliorated by feeding FD rats with the MF and FS diets (P < 0·05). Feeding the FS diet to Aß-injected rats enriched brain folate levels and reduced mtDNA4834 deletion in the hippocampal and medullary regions compared with corresponding tissues of Aß+FD rats (P < 0·05). Aß+FS rats had reduced rates of neuronal death in the frontal cortex compared with Aß+FD rats (P < 0·05). Taken together, our data revealed that folate deprivation differentially depleted brain folate levels, and increased lipid peroxidation and mtDNA4834 deletions, particularly, in the hippocampus. Upon Aß challenge, the FS diet may protect various brain regions against lipid peroxidation, mitochondrial genotoxicity and neural death associated with folate deprivation.

The isolated and combined effects of folic acid and synthetic bioactive compounds against Abeta(25-35)-induced toxicity in human microglial cells.

Folic acid plays an important role in neuronal development. A series of newly synthesized bioactive compounds (NSCs) was reported to exhibit immunoactive and neuroprotective functions. The isolated and combined effects of folic acid and NSCs against beta-amyloid (Abeta)-induced cytotoxicity are poorly understood. These effects were tested using human microglia cells (C13NJ) subjected to Abeta(25-35) challenge. According to an MTT assay, treatment of C13NJ cells with Abeta(25-35) at 10-100 microM for 48 h induced 18%-43% cellular death in a dose-dependent manner (p < 0.05). Abeta(25-35) treatment at 25 microM induced nitrite oxide (NO) release, elevated superoxide production, and reduced the distribution of cells in the S phase. Preincubation of C13NJ with 100 microM folic acid protected against Abeta(25-35)-induced cell death, which coincided with a reduction in NO release by folic acid supplements. NSC47 at a level of 50 microM protected against Abeta(25-35)-induced cell death and reduced Abeta-promoted superoxide production (p < 0.05). Folic acid in combination with NSC47 at their cytoprotective doses did not synergistically ameliorate Abeta(25-35)-associated NO release, superoxide production, or cell cycle arrest. Taken together, folic acid or NSC treatment alone, but not the combined regimen, protected against Abeta(25-35)-induced cell death, which may partially, if not completely, be mediated by free radical-scavenging effects.