Blocking a Single Protein Could Prevent Nerve Damage Responsi-

ble For Alzheimer’s

Scientists have identified a key protein in the development of Alzheimer's disease which could prove critical in slow-
ing or even halting the condition's progress.
In tests on mice, a research team led by University of Colorado pharmacologist Tyler Martinez found that blocking a
protein called murine double-minute 2 (Mdm2) stopped the destruction of the protrusions or 'dendritic spines' and
junctions (synapses) that aid communication between brain cells.
This degeneration is triggered by the build-up of a substance called amyloid-beta, which has long been linked to clog-
ging up the brain in people with Alzheimer's. When Mdm2 was deactivated, amyloid-beta no longer had the same ef-
fect.

"When this protein Mdm2 is turned on inappropriately, it leads to pruning of the synapses when amyloid-beta is
present," says neuroscientist Mark Dell'Acqua, from the University of Colorado.

"When we used the drug that inhibits Mdm2 on the neurons, it completely blocked dendritic spine loss triggered by
amyloid-beta. So inhibiting this protein is clearly working."

While a certain quantity of amyloid-beta and the trimming of dendritic spines serve important functions in a healthy
body, problems happen when they get out of control. Understanding the first links in that chain is likely to be crucial
in understanding Alzheimer's.

The neurological communications handled by dendritic spines and synapses are crucial in our ability to learn and re-
member – and in Alzheimer's, those functions are significantly impaired, due to the breakdown in the brain's signal-
ing.

In this study, the experimental cancer drug nutlin was used to limit Mdm2 activity, which itself usually plays a signifi-
cant role in tumor suppression. It's still early days for this particular area of research, but what the researchers have
seen in mouse brains looks promising.
"This is an encouraging first step that gives us a new lead to pursue," says Dell'Acqua.

The next stage would be to see if the effects of inhibiting Mdm2 really do slow Alzheimer's down. It's a complex and
multi-faceted disease, and while amyloid-beta proteins are chief suspects in the hunt for a cause, there's not enough
evidence yet for a conviction.

Researchers continue to make new discoveries about how Alzheimer's gets started and goes on to impact the brain,
and it's possible that the rest of the body is involved too – something that the team behind this latest study is ready to
acknowledge.

"There are questions if anti-amyloid therapy is the be-all and end-all of Alzheimer's disease therapy," says Dell'Acqua.
"Even if you could tolerate the high cost, the effectiveness is questionable."

"We are saying that it may also be possible to intervene in the process by blocking some of the impacts of amyloid-b.
And you could intervene by targeting Mdm2."
The research has been published in eNeuro.