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MGH Research Targets Proteins' Roles in Hastening Dementia, Dealing with Stress: Studies look at one protein's role in the stress response and how CVD risk factors interact with a protein linked to Alzheimer's.

Two recent studies by Massachusetts General Hospital (MGH) researchers may help doctors move closer toward lowering the risks of Alzheimer's disease and stress-related conditions, such as depression and post-traumatic stress disorder (PTSD).

In one study, published recently in JAMA Neurology, MGH researchers found that the risk for cognitive decline in older adults may be hastened in people with certain risk factors for heart disease and stroke and who have higher levels of beta-amyloid--the brain protein associated with Alzheimer's disease (AD).

A separate study, published in the journal Cell Reports, identified a crucial role for a protein called Kruppel-like factor 9 (Klf9) in the brain's response to stress. Higher levels of Klf9 are associated with stress and conditions such as major depressive disorder and PTSD. Elevated Klf9 levels can affect the hippocampus, the part of the brain where memories are encoded. The researchers suggest that ongoing harm to the hippocampus by high Klf9 levels could impair the brain's ability to process stressful memories. In the study, researchers were able to diminish Klf9 activity in mice, which in turn protected the mice from some of the harmful effects of stress.

Though this was an animal study, researchers are optimistic that their findings will have applications for people dealing with serious stress-related conditions. Other studies suggest that Klf9 levels may affect males and females differently, providing additional areas for Klf9 research. "Our study begins to illuminate the role of Klf9-dependent modulation of neural circuitry as one potential mechanism," says the study's lead author, Amar Sahay, PhD, with the MGH Center for Regenerative Medicine and Department of Psychiatry. 'A greater understanding of how Klf9 exerts these effects--which we hope to pursue--may identify treatment targets that confer resilience to stress for both women and men."

Heart-Brain Connection

How to bolster the brain's resilience against cognitive decline was the goal of a separate MGH study. Researchers wanted to find other mechanisms that might accelerate the onset of AD in people with beta-amyloid plaques on nerve cells in the brain. Having high levels of beta-amyloid is a characteristic of AD. Beta-amyloid fragments come from a protein found in the fatty membrane that surrounds nerve cells. It appears beta-amyloid plaques block the communication between nerve cells and may activate the body's immune system cells to trigger inflammation and destroy disabled nerve cells.

However, some people have beta-amyloid plaques, but don't develop

Alzheimer's. This led researchers to search for other markers beyond beta-amyloid to help identify people at risk for cognitive decline. The MGH researchers wanted to know whether cardiovascular risk factors simply added to the risk posed by plaque build-up, or whether there was an interaction between the two that produced an even higher level of risk. Researchers found that there did indeed appear to be a synergistic relationship.

"Our findings suggest that having vascular risk factors like diabetes, smoking, and high blood pressure may accelerate the rate of cognitive decline in normal older adults, and that the effect of vascular risk on decline is magnified in people with higher brain amyloid levels," says Jennifer Rabin, PhD, a clinical and research fellow with the MGH Department of Psychiatry and lead author of the study. "Our findings support the rationale behind targeting modifiable vascular risk factors either alone or in combination with amyloid-lowering therapies to delay cognitive decline. Measures of vascular risk also may be able to complement existing biomarkers in identifying people at the greatest risk of cognitive decline."

The study found that even moderate vascular risk factors can interact with beta-amyloid to advance cognitive decline. Corresponding study author Jasmeer Chhatwal, MD, PhD, of the MGH Department of Neurology, suggests that this research is further evidence that what is good for the heart is good for the brain. Keeping blood glucose, blood pressure, and cholesterol levels in healthy ranges may benefit both cardiovascular and cognitive health in the long term.

"We can reduce vascular risk factors through medical treatments and lifestyle interventions, and reducing these vascular risk factors might reduce memory loss over time--especially in people with high brain amyloid," Dr. Chhatwal says.
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Title Annotation:Massachusetts General Hospital; cardiovascular disease; Kruppel-like factor 9
Publication:Mind, Mood & Memory
Date:Aug 1, 2018
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