08 Jul 2003

Just grind some dehydrated blueberries into your people-chow and counteract the effects of aging and Alzheimer's disease on memory. That's one hypothesis we can take away from a recent study by Jim Joseph and colleagues, wherein they show that blueberries helped APP/PS-1 transgenic mice achieve memory tests results comparable to wild-type mice. And that benefit does not seem to depend on any reduction in β-amyloid (Aβ) burden.

Joseph and his colleagues at the USDA Human Nutrition Research Center on Aging at Tufts University have looked into the health benefits of various plant products that are high in antioxidant polyphenols. Blueberries are at the top of the list. Joseph's group has found evidence that blueberry supplementation could reverse cognitive, motor learning, and neuronal signaling deficits in normal aged mice (Joseph et al., 1999).

In the present paper, published in the June issue of Nutritional Neuroscience, Joseph and colleagues describe their work with double-transgenic mice (APP KM670/671NL [Swedish] and PS-1 M146L) bred by coauthors Dave Morgan and Marcia Gordan at the University of South Florida. From four to 12 months of age, some of the mice were fortunate enough to eat mouse chow that included blueberry extract. At 12 months of age, these double-transgenic mice are expected to have high brain burdens of Aβ, and Joseph and colleagues confirmed this, even in the mice that had been eating blueberries. However, the fructivorous mice did not have the same memory deficits as normally fed APP/PS-1 mice, as measured on a Y maze task. Indeed, they performed at levels comparable to wild-type mice.

If the blueberry extract did not impact Aβ fibrillization or deposition, then where could the memory benefit have come from? To address the possibility that some components of blueberries impact neuronal signaling, the authors assayed a number of proteins involved in signaling. Compared to both wild-type and APP/PS-1 mice on normal diet, the blueberry-fed transgenic mice had significant increases in activity of carbochol-stimulated GTPase and hippocampal ERK and PhPKC-α. The blueberry supplementation also reduced the activity of N-Sase, an enzyme that makes cells more vulnerable to oxygen free radicals.

"Taken on face value, these data would implicate a nondepositing pool of Aβ that is sensitive to the antioxidant effects of the supplemented diet and is more closely linked to the memory deficits in these animals than the forms detected using Aβ immunochemistry or Congo red histochemistry. If similar mechanisms are at work in humans with dementia, treatments such as that described here may be able to reverse some of the memory impairment without requiring reduction in deposited amyloid," write the authors.-Hakon Heimer.

Reference:
Joseph JA, Denisova NA, Arendash G, Gordon M, Diamond D, Shukitt Hale B, Morgan D. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci. 2003 Jun;6(3):153 62. Abstract

Q&A with Jim Joseph

Q: Tell us a little about what is in blueberries and similar plant products that seems to be beneficial for our neurons.
A: There are probably hundreds of compounds, some of which we don't even know about yet. One group that stands out, because it gives blueberries their color, is the anthocyanins. They're also in strawberries and raspberries. Then there's resveratrol ... proanthicyanidin ...another class called hydroxycynnamates ... phenolic acids. We think they act synergistically to get into the brain. We know that anthocyanins can get past the blood-brain barrier into the brain when they're hooked to sugars-galactosides or glucosides. We don't know if there are other molecules that act as chaperones.

Q: Once in the brain, what molecular effects do these compounds have?
A:: We think they have not only antioxidant effects, but antiinflammatory effects, and even alter neuronal signaling. In standard tests of antioxidant effects, we know that the individual compounds, as well as blueberries themselves, have very high antioxidant activities. Other researchers have looked at some of the same compounds derived from other plants and shown antiinflammatory effects, and we see than in our lab, too.

Q: Did you see this in the APP/PS-1 transgenic mice in this recent study?
A: We didn't look specifically at antioxidant or antiinflammatory effects. We looked at neuronal signaling properties. This particular study told us that, while there's not necessarily a deficit in some of these parameters in these mice, the blueberry diet was able to enhance some of them. We think that by enhancing the signaling, we're able to take advantage of what the brain has left to offset what might be going on with respect to amyloid plaques. If, in fact, these plaques are toxic.

Q: I had heard that you weren't a member of the choir of the "Church of the Holy Amyloid." Yet you're using the Ab mouse model here. Has there been any change in your position?
A: Not really. Now Dave Morgan, whom I'm working with-he's a bishop in the church, but I won't make any more wisecracks with the tape recorder on.

One of the issues with these mice, as opposed to what you see in Alzheimer's disease, is that the mice don't lose neurons. From what I hear, the triple-transgenic mouse, which adds a tau mutation, has actual neuronal deterioration. But just producing plaques in the brain does not produce neuronal loss. This leads one to believe that although Ab may be necessary for the disease, it sure isn't sufficient. Many people think that's a closed argument, and it's really not.

Q: So you weren't surprised that you got memory benefits and signaling alterations without a reduction in Ab?
A: I really didn't know what to expect. I had a feeling it would prevent the behavioral changes from taking place and enhance signaling. I didn't know what it would do to the plaques. My feeling is that it will be hard to find something that actually "gets rid" of the plaques, short of the Ab vaccine. And if you look at some of Mark Smith's work, and what happened in the Elan trial, that may not be all that desirable.

Q: Are the blueberry components affecting a particular pool of Ab?
A: I don't know if the blueberries are doing anything to either soluble Ab or fibrillized Ab. Recent work from Alan Butterfield and others suggests that fibrillar Ab is not the culprit here-it's the soluble Ab. The problem is that the field changes its mind on this issue from week to week, it seems. Maybe we should focus less on the plaques and instead try to enhance the functioning that's left. Maybe that would put the disease on a plateau for four to five years. At least until someone has developed a better way to clear plaques.

Q: Are berry components beneficial for other neurodegenerative diseases?
A: I don't know how many other diseases have been looked at, but every major disease that you could think of, especially those with an age-related component, all tend to feature oxidative stress. I think there's indirect evidence from Rob Friedland's lab showing that people who eat a lot fruits and vegetables are less likely to develop Alzheimer's disease. If you look at groups who practice vegetarianism, they seem to have less morbidity-for example, AD or cardiovascular disease-than groups who have fewer fruits and vegetables in their diet.

The problem with the field has been the thinking that if we deal with the amyloid, we'll prevent or cure the disease. That basically hasn't worked. I think we have to deal with the aging. If you can push the deterioration that occurs with aging out further, I think you will forestall the development of this disease.

Q: Do you have any other blueberry news that you'd like to tell us about?
A: Gemma Casadesus [of Case Western] presented evidence at last year's Society for Neuroscience meeting of neurogenesis in older mice being enhanced with the blueberries. That's being prepared for publication. We think it activates ERK, which probably activates some portion of the BDNF pathway.

Q: Our editor, Gabrielle Strobel, mentioned at a recent meeting that you said you like to make a blueberry smoothie in the morning. What goes in it? A: About a cup of berries, usually frozen blueberries. A couple of scoops of soy or whey protein, some water, a banana and whatever else-cherries, grapes, kiwi, etc. If you use frozen berries, you don't need to add ice.

Q: With other healthy foods like spinach, broccoli, etc., the daily consumption needed to get a real benefit is sometimes quite high. Is a daily smoothie enough to really pack a punch?
A: No. To get five to 10 servings a day takes more than a smoothie, but a smoothie is a good start.

Q: Do you have any other healthful recipes you'd like to share with us?
A:Grilled salmon and veggies. Take the salmon, cut small slits in it and put thin slices of garlic in the slits. Rub the salmon with olive oil and a bit of old bay seasoning and grill it. Take sliced eggplant and red peppers (mild) and marinate them in soy sauce and balsamic vinegar and grill them, as well.

For a salad, wash baby spinach leaves (even if the package says triple-washed), crumble feta cheese on top with some sliced grape tomatoes and walnuts. Add balsamic vinegar to taste.

Finish off the meal with FRESH BERRIES!

Comments

- Wallace Dembski
- Posted: 19 Jul 2003
GREAT!

View all comments by Wallace Dembski

- Gemma Casadesus
  CWRU
- Posted: 04 Aug 2003
Dietary Antioxidants and Alzheimer Disease Gemma Casadesus, Mark A. Smith and George Perry

While little is known about the mechanisms responsible for the neuronal degeneration seen during Alzheimer’s disease (AD), the progressive, age-related inability of the brain to cope with insults such as oxidative stress may provide a fertile environment for the subsequent development of neurodegenerative disease. In this light, preventative benefits might be achieved through the administration of antioxidant or antiinflammatory agents. In a recent article (Joseph et al., 2003), long-term dietary supplementation with blueberries, a fruit rich in antioxidants, afforded considerable improvements, biochemical as well as behavioral, in the AbPP/PS1 transgenic mouse model of AD. Interestingly, the signaling and behavioral improvements produced by blueberry supplementation in these transgenic animals were not associated with any changes in amyloid-b. This is an exciting finding, since it suggests that cognitive and neuronal changes seen in AD may occur independently of amyloid-b production and deposition. This finding supports challenges to the amyloid-centric view of neurodegeneration (Smith et al., 2002) and suggests that therapeutic efforts targeted towards oxidative stress, or the sources thereof, may provide greater benefit than will the removal of amyloid (Perry et al., 2000). Indeed, previous studies show that diets rich in fruits and vegetables protect our brains from neurodegenerative changes and prevent AD (Smith et al., 1999; Engelhart et al., 2002).

References:

Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, Breteler MM. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002 Jun 26;287(24):3223-9. PubMed.

Joseph JA, Denisova NA, Arendash G, Gordon M, Diamond D, Shukitt-Hale B, Morgan D. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci. 2003 Jun;6(3):153-62. PubMed.

Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. PubMed.

Smith MA, Petot GJ, Perry G. Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer's disease. J Alzheimers Dis. 1999 Nov;1(4-5):203-6. PubMed.

Perry G, Nunomura A, Raina AK, Smith MA. Amyloid-beta junkies. Lancet. 2000 Feb 26;355(9205):757. PubMed.

View all comments by Gemma Casadesus

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