Joseph, JA B. and Shukitt-Hale USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111;
Numerous epidemiological studies have indicated that individuals who consume a diet containing high amounts of fruits and vegetables may prevent age-related disease such as Alzheimer Disease. Research from our laboratory has suggested that dietary supplementation with berryfruit extracts high in antioxidants (e.g., blueberry, BB) can decrease the enhanced vulnerability to oxidative stress (OS) that occurs in aging and these reductions are expressed as improvements in behavior. In addition to their antioxidant and anti-inflammatory activities, there appear to be additional multiple mechanisms involved in the beneficial effects observed from these supplementations. These mechanisms include enhancement of neuronal communication that involves increased signaling and neurogenesis. For example, collaborative work with Dr. David Morgan at the University of So. Florida shows that BB supplementation from 4 to 12 months of age in APP/PS1 mice can offset the putative deleterious consequences of amyloid beta deposition on behavior in APP/PS-1 mice by increasing extracellular signal regulated kinase (ERK) and protein kinase C, two important signaling factors in learning and memory. These same MAP kinases also appeared to be activated in learning in both aged and young rats, are enhanced by blueberry supplementation, and are correlated with behavioral performance. It also appears that polyphenolic compounds, such as those found in BB may exert their beneficial effects by enhancing the endogenous antioxidant and neuronal signaling capabilities of the organism. In addition, collaborative work with Dr. Gemma Casadesus from Case Western Reserve Univ. has indicated that one of the most striking effects of BB supplementation may involve increases in neurogenesis MAP kinase signaling and IGF-1 in the dentate gyrus that were associated with a reduced number of errors on the radial arm water maze (RAWM). Additional research showed that the number of errors made by senescent animals on a Morris water maze were inversely correlated with the number of anthocyanins that were localized in regions such as the cortex and hippocampus in the BB-supplemented animals. Taken together, these findings, along with those showing similar beneficial effects on MAP kinase and IGF-1 signaling and behavior in BB-supplemented animals, suggest that antioxidant-rich fruits such as BBs may improve cognitive and motor function by enhancing neuronal signaling and ultimately, neuronal communication. Clearly, however, the antioxidant/anti-inflammatory effects of the berryfruit polyphenols may only represent a small aspect of their beneficial effects. Moreover, recent data in our COS-7 cell model suggest that rather than acting only as free radical scavengers BB polyphenolic compounds may act to turn off several molecular signals (e.g., cyclic AMP response element binding protein; protein kinase C) associated with oxidative stress and to turn on signals which are protective such as MAP kinase. Additionally, data from BV-2 mouse microglia cells suggest that pre-treatment of the cells with BB protects the cells against lipopolysaccharide (an inflammatory agent) by reducing nitrite production. Similar findings were seen in BB-fed young animals given hippocampal kainic acid (an inflammatory mediator) injections which showed decreased expression of cytokines, and NfκB and increased IGF-1. These findings and those above indicate that some of the most significant effects of BB polyphenolics may involve reductions in signals that are turned-on during inflammation or oxidative stress and enhancement of that are protective e.g., IGF-1 and MAP kinase). It may be that we can take advantage of these properties of BB to target specific areas of the signaling pathways to alter reseponses to stress and learning and memory.
Keywords: blueberries, aging, brain, oxidative stress, neurogenesis, inflammation and signaling