Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3′-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.
Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.
The data are consistent with the hypothesis that cytokine expression may differentially contribute to the vulnerability of independent cortical regions during the clinical progression of AD and suggest that an inflammatory cytokine response to the pathological effects of AD does not occur until the late stages of the disease. These findings have implications for the design of anti-inflammatory treatment strategies. Arch Neurol. 2000;57:1153-1160
Several epidemiologic studies have reported that cyclooxygenase (COX) inhibitors prevent/delay the onset of Alzheimer's disease (AD). Recent experimental studies suggest that these compounds can also diminish amyloidβ (Aβ) neuropathology in rodent models of AD. To explore the relationship of COX expression to Aβ neuropathology, we crossed mice expressing both mutant amyloid precursor protein [K670N/M671L (APP swe )] and mutant PS1 (A246E) with mice expressing human COX-2 selectively in neurons. We show here that human COX-2 expression in APP swe /PS1/COX-2 mice induces potentiation of brain parenchymal amyloid plaque formation and a greater than twofold increase in prostaglandin E 2 production, at 24 months of age. This increased amyloid plaque formation coincided with a preferential elevation of Aβ 1-40 and Aβ 1-42 with no change in total amyloid precursor protein (APP) expression/content in the brain. Collectively these data suggest that COX-2 influences APP processing and promotes amyloidosis in the brain. COX-2Amyloid Alzheimer's disease Inflammation A large number of epidemiological studies have indi-(14,21) have shown that COX-2 expression is elevated in the AD brain and that this elevation is corre-cated that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent or delay the clinical fea-lated with the severity of brain amyloid plaque pathology (6). Additionally, a recent study found a tures of Alzheimer's disease (AD) (7,13,18). However, recent therapeutic studies with both cyclooxygenase preferential loss of hippocampal COX-2-immunopositive neurons in the brains of AD patients suffering (COX)-inhibiting NSAIDs and steroids could not confirm this epidemiological evidence (9).severe dementia (22). However, recent evidence indicates that nonselective COX, rather than selective The pharmacological activity of NSAIDs is generally attributed to the inhibition of COX, a rate-limit-COX-2-specific inhibitors, has been found to influence amyloid precursor protein (APP) processing. ing enzyme necessary for the production of prostaglandins (PGs). COX-2 is the inducible form of COX Thus, the characterization of COX activities in the brain and their role in AD amyloidosis is receiving a and is involved in inflammatory responses but also neuronal functions (22). We (5,6,15) and others great deal of attention.
BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism.ResultsIn this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord.ConclusionOur results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.
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