Improving brain function in Alzheimer's disease mouse model

April 11, 2018 by Graciela Gutierrez, Baylor College of Medicine

Using two complementary approaches to reduce the deposits of amyloid-beta in the brain rather than either approach alone improved spatial navigation and memory in a mouse model of Alzheimer's disease. These findings suggest that similar combination treatments also might help patients with Alzheimer's disease in the future. The study appears in the Journal of Experimental Medicine.

"Many of the therapies that are currently being developed to treat Alzheimer's disease focus on reducing the levels of amyloid-beta," said corresponding author Dr. Joanna Jankowsky, associate professor of neuroscience, molecular and cellular biology, neurology, and neurosurgery at Baylor College of Medicine. "Amyloid-beta is a small protein that is abundant in the that characterize Alzheimer's disease."

All previous designed to reduce the levels of amyloid-beta using one therapy at a time have had limited success. Jankowsky and her colleagues have previously shown that combining two complementary treatments to reduce amyloid-beta not only curbs further plaque growth, but also helps to clear plaques that have already formed. With a combination approach, animals finished the study with less amyloid than they had at the start of . In this study, Jankowsky and colleagues determined for the first time the benefits of dual amyloid-beta treatment on brain functions, such as and memory, in a of Alzheimer's disease.

Two is better than one

To reduce the levels of amyloid-beta the researchers attacked the problem from two fronts. On one front, they worked with a mouse model genetically engineered to stop the production of amyloid-beta. On the other front, they promoted the elimination of amyloid-beta with antibodies that bind to this protein and promote its elimination.

"Using this combined approach, we were able to reduce the levels of amyloid-beta, but, importantly, restored spatial learning and memory to the level observed in healthy mice," Jankowsky said.

The other contribution of this study was the identification of potential alternative therapeutic targets.

"Dr. Angie Chiang, a recent Ph.D. graduate from my lab and the first author of this work, was interested in identifying a molecular mechanism supporting our observations and decided to look at the mTOR pathway," Jankowsky said.

The mTOR protein is part of a complex that carries out a multitude of functions within cells, including the formation of synapses –– the connections between neurons–– their maintenance and plasticity. This pathway also regulates autophagy, one of the cellular processes that eliminates amyloid-beta. The mTOR pathway sits at the intersection of these processes that Jankowsky and her colleagues found changed as a result of treatment.

"The neurons had roadblocks that were causing them to swell and malfunction; the double treatment helped clear that roadblock," Jankowsky said. "Also, synapses lost as a result of the were rebuilt, and the animals improved learning and memory."

The researchers showed that the mTOR pathway correlates with brain improvements observed in their mice and suggest that future studies might test whether the pathway is necessary to mediate such improvements.

"If mTOR signaling is necessary for the improvements, it might become an alternative target for combination therapy," Jankowsky said. "We hope that our findings will be valuable in discussions about future human clinical trials."

Explore further: Alzheimer's proteins in ICU survivors

More information: Angie C.A. Chiang et al. Combination anti-Aβ treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice, The Journal of Experimental Medicine (2018). DOI: 10.1084/jem.20171484

Related Stories

Alzheimer's proteins in ICU survivors

March 29, 2018
While modern medicine has increased the number of people who survive a stay in the Intensive Care Unit (ICU), survivors have a high risk of developing problems with thinking and memory, a phenomenon called cognitive impairment.

Researchers successfully reverse Alzheimer's disease in mouse model

February 14, 2018
A team of researchers from the Cleveland Clinic Lerner Research Institute have found that gradually depleting an enzyme called BACE1 completely reverses the formation of amyloid plaques in the brains of mice with Alzheimer's ...

Different disease types associated with distinct amyloid-beta prion strains found in Alzheimer's patients

January 9, 2018
An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National ...

Key cellular auto-cleaning mechanism mediates the formation of plaques in Alzheimer's brain

October 3, 2013
Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer's disease. It might be a potential drug target for the treatment of the disease, concludes ...

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Never before seen images of early stage Alzheimer's disease

March 13, 2017
Researchers at Lund University in Sweden have used the MAX IV synchrotron in Lund – the strongest of its kind in the world - to produce images that predate the formation of toxic clumps of beta-amyloid, the protein believed ...

Recommended for you

Amyloid pathology transmission in lab mice and historic medical treatments

December 13, 2018
A UCL-led study has confirmed that some vials of a hormone used in discontinued medical treatments contained seeds of a protein implicated in Alzheimer's disease, and are able to seed amyloid pathology in mice.

Study links slowed brainwaves to early signs of dementia

December 13, 2018
To turn back the clock on Alzheimer's disease, many researchers are seeking ways to effectively diagnose the neurodegenerative disorder earlier.

New discoveries predict ability to forecast dementia from single molecule

December 11, 2018
Scientists who recently identified the molecular start of Alzheimer's disease have used that finding to determine that it should be possible to forecast which type of dementia will develop over time—a form of personalized ...

Researchers classify Alzheimer's patients in six subgroups

December 5, 2018
Researchers studying Alzheimer's disease have created an approach to classify patients with Alzheimer's disease, a finding that may open the door for personalized treatments.

Neuroscientists pinpoint genes tied to dementia

December 3, 2018
A UCLA-led research team has identified genetic processes involved in the neurodegeneration that occurs in dementia—an important step on the path toward developing therapies that could slow or halt the course of the disease. ...

Detecting signs of neurodegeneration earlier and more accurately

November 30, 2018
Signs of neurodegenerative diseases, appearing years before the emergence of clinical manifestations, can be detected during the examination of medical samples by means of fluorescence microscopy by using new sensitive and ...

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.