February 13, 2018

Compound repairs features of Alzheimer’s disease in mice

At a Glance

  • Researchers found that a compound called an NAD+ precursor helped mice with features of Alzheimer’s disease perform better on learning and memory tests.
  • The findings pave the way for studies of the compound’s potential as an intervention for people with Alzheimer’s disease.
Mouse brain with hallmarks of Alzheimer’s disease A mouse brain showing hallmarks of Alzheimer’s disease similar to that of the mice used in this study. Abnormal protein clumps are blue, blood vessels are red, and nerve cells are green.Alvin Gogineni, Genentech

Alzheimer’s disease is a brain disorder that slowly destroys thinking, memory, and language skills. It’s the most common cause of dementia among older people. Experts estimate that more than 5 million Americans are living with the disease. Symptoms usually begin after age 60. There is no cure.

The brain’s usual DNA repair activity is impaired in Alzheimer’s disease, leading to inflammation and dysfunction. A compound that the brain needs to regulate DNA repair and other key signaling pathways is known as nicotinamide adenine dinucleotide (NAD+). Because NAD+ declines with age, scientists have wondered whether boosting the level of NAD+ could help aging brain cells (neurons) to function better. One way to increase the cellular level is by giving an NAD+ precursor compound, such as nicotinamide riboside (NR). NR is a form of vitamin B3.

An international research team led by Dr. Vilhelm A. Bohr at NIH’s National Institute on Aging (NIA) set out to test whether NR supplements could normalize NAD+ levels in the brains of mice and counteract deficits in thinking and memory. The study was published online on February 5, 2018, in the Proceedings of the National Academy of Sciences.

The research team used findings from their previous studies with human cadaver brain tissue to develop a new strain of mice. These mice had the main features of human Alzheimer’s disease, such as the abnormal buildup of the proteins tau and amyloid-beta. The research team added the NR supplement to the mice’s drinking water for three months.

The team found that the NR-treated mice had less DNA damage, lower levels of neuron damage and death, increased production of new neurons, and lower brain inflammation than control mice. Mice who received NR had reduced tau in their brains, too, but amyloid-beta levels were unchanged. The NR-treated mice performed better than control mice on many learning and memory tests, such as a water maze. In addition, NR-treated mice had better muscle strength and endurance than controls.

The research team also tested human cells from people with and without Alzheimer’s disease. As in the mouse studies, NR decreased DNA damage in the cells from people with Alzheimer’s.

“The pursuit of interventions to prevent or delay Alzheimer’s and related dementias is an important national priority,” says NIA Director Dr. Richard J. Hodes. “We are encouraging the testing of a variety of new approaches, and this study’s positive results suggest one avenue to pursue further.”

“We are encouraged by these findings that see an effect in this Alzheimer’s disease model,” Bohr says. “We are looking forward to further testing of how NR or similar compounds might be pursued for their possible therapeutic benefit for people with dementia.”

The team is continuing to study the biological mechanisms of Alzheimer’s disease in preparation for possible studies of the approach in people.

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References: NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Yujun Hou, Sofie Lautrup, Stephanie Cordonnier, Yue Wang, Deborah L. Croteau, Eduardo Zavala, Yongqing Zhang, Kanako Moritoh, Jennifer F. O’Connell, Beverly A. Baptiste, Tinna V. Stevnsner, Mark P. Mattson and Vilhelm A. Bohr. PNAS 2018; published ahead of print February 5, 2018, https://doi.org/10.1073/pnas.1718819115 .

Funding: NIH’s National Institute on Aging (NIA) and ChromaDex.