Study identifies protein that contributes to cognitive decline in Alzheimer's

June 25, 2013

Researchers at Columbia University Medical Center (CUMC) have demonstrated that a protein called caspase-2 is a key regulator of a signaling pathway that leads to cognitive decline in Alzheimer's disease. The findings, made in a mouse model of Alzheimer's, suggest that inhibiting this protein could prevent the neuronal damage and subsequent cognitive decline associated with the disease. The study was published this month in the online journal Nature Communications.

One of the earliest events in Alzheimer's is of the brain's (the small gaps across which are passed), which can lead to . Although what drives this process has not been clear, studies have indicated that caspace-2 might be involved, according to senior author Michael Shelanski, MD, PhD, the Delafield Professor of Pathology & Cell Biology, chair of the Department of & Cell Biology, and co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC.

Several years ago, in tissue culture studies of mouse neurons, Dr. Shelanski found that caspace-2 plays a critical role in the death of neurons in the presence of amyloid beta, the that accumulates in the neurons of people with Alzheimer's. Other researchers have shown that caspase-2 also contributes to the maintenance of normal synaptic functions.

Dr. Shelanski and his team hypothesized that aberrant activation of caspase-2 may cause synaptic changes in Alzheimer's disease. To test this hypothesis, the researchers crossed J20 transgenic mice (a common of Alzheimer's) with caspase-2 null mice (mice that lack caspase-2). They compared the animals' ability to negotiate a radial-arm water maze, a standard test of cognitive ability, with that of regular J20 mice and of normal mice at 4, 9, and 14 months of age.

The results for the three groups of mice were similar at the first two intervals. At 14 months, however, the J20/caspase-2 null mice did significantly better in the water maze test than the J20 mice and similarly to the normal mice. "We showed that removing caspase-2 from J20 mice prevented memory impairment—without significant changes in the level of soluble amyloid beta," said co-lead author Roger Lefort, PhD, associate research scientist at CUMC.

Analysis of the neurons showed that the J20/caspase-2 null mice had a higher density of dendritic spines than the J20 mice. The more spines a neuron has, the more impulses it can transmit.

"The J20/caspase-2 null mice showed the same dendritic spine density and morphology as the normal mice—as opposed to the deficits in the J20 mice," said co-lead author Julio Pozueta, PhD. "This strongly suggests that caspase-2 is a critical regulator in the memory decline associated with beta-amyloid in Alzheimer's disease."

The researchers further validated the results in studies of rat neurons in tissue culture.

Finally, the researchers found that caspase-2 interacts with RhoA, a critical regulator of the morphology (form and structure) of dendritic spines. "It appears that in normal neurons, caspase-2 and RhoA form an inactive complex outside the dendritic spines," said Dr. Lefort. "When the complex is exposed to amyloid beta, it breaks apart, activating the two components." Once activated, caspase-2 and RhoA enter the dendritic spines and contribute to their demise, possibly by interacting with a third molecule, the enzyme ROCK-II.

"This raises the possibility that if you can inhibit one or all of these molecules, especially early in the course of Alzheimer's, you might be able to protect neurons and slow down the cognitive effects of the disease," said Dr. Lefort.

Explore further: New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

More information: The paper is titled, "Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice."

Related Stories

New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

June 19, 2013
For years, Alzheimer's researchers have focused on two proteins that accumulate in the brains of people with Alzheimer's and may contribute to the disease: plaques made up of the protein amyloid-beta, and tangles of another ...

Study unravels central mystery of Alzheimer's disease

April 10, 2013
Scientists at The Scripps Research Institute (TSRI) have shed light on one of the major toxic mechanisms of Alzheimer's disease. The discoveries could lead to a much better understanding of the Alzheimer's process and how ...

Link between inflammatory process and progression of Alzheimer's disease

December 19, 2012
An international team of researchers from the University of Massachusetts Medical School, the University of Bonn and the Center for Advanced European Studies and Research in Germany have shown that a well-known immune and ...

Stress hormone could trigger mechanism for the onset of Alzheimer's

June 21, 2013
(Medical Xpress)—A chemical hormone released in the body as a reaction to stress could be a key trigger of the mechanism for the late onset of Alzheimer's disease, according to a study by researchers at Temple University.

Innovative method to treat Alzheimer's in mice

April 1, 2013
Researchers from the RIKEN Brain Science Institute report that they successfully used a virus vector to restore the expression of a brain protein and improve cognitive functions, in a mouse model of Alzheimer's disease.

Drug reverses Alzheimer's disease deficits in mice, research confirms

May 23, 2013
An anti-cancer drug reverses memory deficits in an Alzheimer's disease mouse model, University of Pittsburgh Graduate School of Public Health researchers confirm in the journal Science.

Recommended for you

Lifestyle changes to stave off Alzheimer's? Hints, no proof

July 20, 2017
There are no proven ways to stave off Alzheimer's, but a new report raises the prospect that avoiding nine key risks starting in childhood just might delay or even prevent about a third of dementia cases around the world.

Blood test identifies key Alzheimer's marker

July 19, 2017
A new study led by researchers at Washington University School of Medicine in St. Louis suggests that measures of amyloid beta in the blood have the potential to help identify people with altered levels of amyloid in their ...

Steering an enzyme's 'scissors' shows potential for stopping Alzheimer's disease

July 19, 2017
The old real estate adage about "location, location, location" might also apply to the biochemical genesis of Alzheimer's disease, according to new research from the University of British Columbia.

Brain scans may change care for some people with memory loss

July 19, 2017
Does it really take an expensive brain scan to diagnose Alzheimer's? Not everybody needs one but new research suggests that for a surprising number of patients whose memory problems are hard to pin down, PET scans may lead ...

Can poor sleep boost odds for Alzheimer's?

July 18, 2017
(HealthDay)— Breathing problems during sleep may signal an increased risk for Alzheimer's disease, a trio of studies suggests.

Hearing is believing: Speech may be a clue to mental decline

July 17, 2017
Your speech may, um, help reveal if you're uh ... developing thinking problems. More pauses, filler words and other verbal changes might be an early sign of mental decline, which can lead to Alzheimer's disease, a study suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.