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At the Bench-Alzheimer's Disease
Exercise Prompts Neurogenesis and Prevents Cognitive Decline in Animal Models of Alzheimer's

ARTICLE IN BRIEF

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INDUCING ADULT HIPPOCAMPAL neurogenesis (AHN) alone by WNT3 and P7C3 together did not prevent cognitive dysfunction, whereas activating AHN through exercise improved memory in transgenic mice. Increasing AHN alone together with overexpression of BDNF could mimic exercise-induced improvement in cognition. Suppressing AHN exacerbated neuronal vulnerability, leading to cognitive impairment and increased neuronal loss in transgenic mice, but not in wild-type mice.

Using gene therapy and pharmacologic agents in animal models of Alzheimer's disease (AD), researchers were able to show how exercise turns on neurogenesis and inhibits cognitive decline, even in the setting of AD pathology.

Nightly rounds of exercise were powerful enough to prevent cognitive decline in animal models of Alzheimer's disease (AD) — even in the presence of AD pathology, according to a September 7 paper in Science. And the team of Harvard scientists figured out why it works.

Exercise has been shown to turn on neurogenesis in the adult brain, but it was not known whether neurogenesis plays a role in AD and how exercise leads to such benefits. A team of scientists, led by senior study author Rudolph E. Tanzi, PhD, director of the genetics and aging research unit, vice-chair of the department of neurology, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH), conducted studies in transgenic AD mouse models that show that exercise can significantly reduce levels of pathological amyloid-beta and improve cognition.

“While we do not yet have the means for safely achieving the same effects in patients, we determined the precise protein and gene targets for developing ways to do so in the future,” said the lead study author Se Hoon Choi, PhD, assistant professor of neurology in the genetics and aging research unit.

STUDY METHODS, FINDINGS

The MGH team set out to investigate how adult hippocampal neurogenesis affects AD pathology and cognitive decline. Their test subjects were transgenic mice destined to develop amyloid-beta pathology and cognitive problems. Generally, the mice start showing signs of cognitive decline (and pathology) at five months old. But many of the AD mice that spent three or four hours a night on a running wheel performed better on a series of cognitive tests. The nightly runners also had reduced amyloid-beta plaques, and the new neurons in the hippocampus survived to become fully functioning nerve cells. (There were a few runners that showed no benefits from exercise.)

The researchers wanted to know how exercise-induced neurogenesis works in the AD brain. The clues would come from genetic and pharmacological techniques that mimic neurogenesis. The scientists used a drug that enhances neurogenesis (P7C3) and a lentivirus that expresses Wnt3, which also enhances neurogenesis. Dr. Tanzi and his colleagues found that both techniques enhanced neurogenesis but neither worked to reduce the pathological accumulation of amyloid-beta protein. The animals also did not show any improvements in cognition.

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DR. RUDOLPH TANZI: “The number of neurons born at six weeks in the hippocampus matters. If we can induce neurogenesis earlier, it may help patients in early stages of Alzheimers.”

They discovered that the missing ingredient produced naturally during exercise — in addition to the cellular events that trigger neurogenesis — is brain-derived neurotrophic factor (BDNF).

To prove their hypothesis that enhancing BDNF was important, the scientists repeated the same genetic and pharmacologic studies but added a gene that turns on BDNF. As they suspected, the overexpression of BDNF on top of either genetically or pharmacologically inducing neurogenesis was enough to dramatically improve cognition. The new neurons matured and survived, and the animals did significantly better on cognitive tests. Studies have shown that BDNF reduces inflammation and helps neurons survive.

BDNF alone is not sufficient to improve cognition or reduce amyloid-beta. And adding BDNF did not lead to a decrease in amyloid-beta, said Dr. Tanzi. “It is not enough just to turn on the birth of new nerve cells, you must simultaneously ‘clean up’ the neighborhood in which they are being born to make sure the new cells survive and thrive. Exercise can achieve that, but we found ways of mimicking those beneficial cognitive effects by the application of drugs and gene therapy that simultaneously turn on neurogenesis and BDNF production.”

In another study, the scientists blocked the birth of new neurons in the hippocampus in mice that were between six to eight weeks old. The mice became cognitively impaired sooner and were worse off later in life. What's more, exercise alone in the AD mice, without the help of increased hippocampal neurogenesis, had no beneficial effects on cognitive function.

“The number of neurons born at six weeks in the hippocampus matters,” said Dr. Tanzi. “If we can induce neurogenesis earlier, it may help patients in early stages of Alzheimer's.”

With this new evidence, Dr. Tanzi and his colleagues want to initiate studies to test the benefits of exercise in patients and whether it would be possible to pharmacologically or genetically manipulate neurogenesis and stimulate BDNF to reduce AD pathology and stave off cognitive decline.

“The results were pursued in such depth and with such persistence until a mechanism responsible for the effects of running was identified,” said Fred H. Gage, PhD, the president of the Salk Institute for Biological Studies and a scientist in the laboratory of genetics. Dr. Gage, who studies neurogenesis, shared his Wnt3 lentivirus with the Mass General team, and is a co-author on the study.

“There are multiple advantages of exercise and just enhancing neurogenesis is not enough,” Dr. Gage said. “An unfavorable environment will not support the function of new neurons. This finding encourages us to think about multi-therapeutic interventions. There will be no single bullet for Alzheimer's.”

The study was supported with grants from the Cure Alzheimer's Fund, the JPB Foundation, the Mather's Foundation, The Leona and Harry Helmsley Charitable Trust, and the National Institutes of Health.

EXPERT COMMENTARY

“Previous studies have shown that exercise stimulates adult hippocampal neurogenesis and improves cognitive function during aging, and that neurotrophic factors such as BDNF are involved in this process,” said David M. Holtzman, MD, FAAN, the Andrew B. and Gretchen P. Jones professor and chairman of neurology at Washington University School of Medicine in St. Louis.

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DR. DAVID M. HOLTZMAN: “These findings are potentially very relevant to future studies in humans. They clearly suggest that exercise may be able to improve cognitive performance in the setting of cognitive impairment due to AD without having to decrease AD pathology.”

“These findings are potentially very relevant to future studies in humans. They clearly suggest that exercise may be able to improve cognitive performance in the setting of cognitive impairment due to AD without having to decrease AD pathology,” Dr. Holtzman said. “Perhaps most importantly, they suggest that increasing adult hippocampal neurogenesis and BDNF, achievable via pharmacological +/- gene therapy or other approaches, is a path to consider in future human therapeutic trials.”

Michelle W. Voss, PhD, agreed. “The findings don't necessarily warrant new recommendations for patients, but do provide important clues for future research,” said Dr. Voss, assistant professor of psychological and brain sciences at the University of Iowa, where she runs a health, brain, and cognition lab. She and her colleagues conduct clinical trials with healthy older adults to understand how exercise affects the hippocampus and how hippocampal connectivity affects learning and memory.

“It is interesting that some of the mice running three hours a day had similar brain and behavioral outcomes as the sedentary animals,” Dr. Voss said. “Similarly, some people just don't respond as well to exercise, and we need to understand why and what is modifiable. It's not just those that can't exercise that could benefit from mimetics — active ‘non-responders’ may benefit too. We're a long way from understanding how this could work, but this study gets us a little closer.”

“This study confirms most of what we already know from past exercise studies in humans and animals,” said Ozioma Okonkwo, PhD, assistant professor at the University of Wisconsin, Madison. Dr. Okonkwo is a site principal investigator for a multicenter 18-month phase 3 study testing the effects of aerobic exercise in people with mild cognitive impairment.

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DR. MICHELLE W. VOSS: “Its not just those that cant exercise that could benefit from mimetics — active ‘non-responders’ may benefit too. Were a long way from understanding how this could work, but this study gets us a little closer.”

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DR. OZIOMA OKONKWO: “I think the biggest take-home message is that we are not at the point yet where we can pop a pill and reap the full benefits of exercise. To paraphrase the well-known real estate mantra, when it comes to preventing AD, perhaps its ultimately all about ‘lifestyle, lifestyle, lifestyle.’”

Dr. Okonkwo said that he would have liked to know whether exercise led to changes in the vasculature of the mouse brains in the exercise arm of the study as “this may have been one of the mechanisms underlying the preferential survival of the newly-born neurons in the exercise arm of the experiment.”

He added: “What is most exciting about the Tanzi study is the rigor with which the investigators tested the various hypotheses. I think the biggest take-home message is that we are not at the point yet where we can pop a pill and reap the full benefits of exercise. To paraphrase the well-known real estate mantra, when it comes to preventing AD, perhaps it's ultimately all about ‘lifestyle, lifestyle, lifestyle.’”

LINK UP FOR MORE INFORMATION:

• Choi SH, Bylykbashi E, Chatila ZK, et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in Alzheimer's mouse model http://science.sciencemag.org/content/361/6406/eaan8821.long. Science 2018: 361(6406): pii:3aan8821.