University of Southern California

USC Neuroscience

On the Hunt

Prof. Caleb Finch
August 29, 2003

The clustering of a common protein may be the cause of Alzheimer's. The discovery by a USC gerontologist and his colleagues could lead to therapeutic drugs that delay the disease's progression and prevent its onset.

On their own they're considered harmless proteins.

But allow a small group of "amyloid beta" molecules to cluster in the brain and you may have the culprit behind Alzheimer's disease, according to new research by a USC gerontologist and his colleagues.

Caleb Finch, holder of the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging at USC, and collaborators from Northwestern University and Acumen Pharmaceuticals have discovered for the first time a toxic protein aggregate believed to be the cause of the mind-debilitating illness.

Their findings, which could lead to therapeutic drugs that delay Alzheimer's progression, prevent its onset and restore cognitive function in patients with memory-related disorders, appear in the Sept. 2 print issue of the journal Proceedings of the National Academy of Science.

"Individual units of amyloid beta protein don't seem to be harmful," said Finch, a co-founder of Acumen. "But get a small cluster of three to 24 units together, and it becomes toxic."

A fundamental finding by the team centers on the link between the size of the amyloid cluster and its toxic punch.

"The toxicity of this protein increases as more units [up to 24] are added to the aggregate," Finch said. "However, once the number of units becomes so great that the cluster becomes rope-like, the toxicity decreases."

While it remains unknown why amyloid molecules cluster in some people's brain tissue yet not in others, the team's current findings bolster a theory it set forth in 1998.

While they concurred with fellow researchers that amyloid beta was to blame for Alzheimer's, the team did not believe that large clumps of amyloid called "fibrils" -- which coalesce in the brain to form larger deposits called plaques -- caused the illness.

For nearly 20 years, researchers believed fibrils and plaques were to blame for Alzheimer's disease because autopsies consistently demonstrated plaques in the brains of victims, and fibrils had been shown to kill nerve cells in laboratory settings.

But Finch and his colleagues hypothesized that a novel form of wadded-up amyloid called "amyloid beta-derived diffusible ligands," or ADDLs, caused the disease.

Unlike bulky fibrils, which are confined to the locations in which they form, ADDLs ("pronounced add-ls") are capable of diffusing everywhere in the brain.