Scientists isolate a toxic key to Alzheimer's disease in human brains

Soluble Beta-Amyloid Protein Fragments May Damage Brain Cell

Dennis Selkoe

Photo by Jon Chase/Harvard News Office

Scientists have long questioned whether the abundant amounts of amyloid plaques found in the brains of patients with Alzheimer's actually caused the neurological disease or were a by-product of its progress. Now, using new research techniques, scientists have shown that a two-molecule aggregate (or dimer) of beta-amyloid protein fragments may play a role in initiating the disease.

The study, by Dennis J. Selkoe of Harvard Medical School and Brigham and Women's Hospital, and colleagues suggests a possible new target for developing drug therapies to combat the irreversible and progressive disorder. The findings have been published as an advance on-line letter by Nature Medicine.

Alzheimer's disease is marked by the build-up of plaques consisting of beta-amyloid protein fragments, as well as abnormal tangles of tau protein found inside brain cells. Early in the disease, Alzheimer's pathology is first observed in the hippocampus, the part of the brain important to memory, and gradually spreads to the cerebral cortex, the outer layer of the brain.

In this study, in which the Harvard and Brigham team collaborated with other Harvard researchers and scientists at University College Dublin, Beaumont Hospital and Royal College of Surgeons Ireland, and Trinity College Dublin, Ireland, researchers tested cerebral cortex extracts from brains donated for autopsy by people aged 65 and older with Alzheimer's and other dementias, as well as those without dementia. The extracts contained soluble one-molecule (monomer), two-molecule (dimer), three-molecule (trimer) or larger aggregates of beta-amyloid, as well as insoluble plaque cores. The researchers then injected the extracts into normal rats or added the extracts to slices of normal mouse hippocampus.

Selkoe, lead author Ganesh M. Shankar and colleagues discovered that both the soluble monomers and the insoluble plaque cores had no detectable effect on the hyppocampal slices. However, the soluble dimers induced certain key characteristics of Alzheimer's in the rats. The dimers impaired memory function, specifically the memories of newly learned behaviors.

In the mouse hippocampal slices, the dimers also reduced by 47 percent the density of the dendrite spines that receive messages sent by other brain cells. The dimers seemed to be directly acting on synapses, the connections between neurons that are essential for communication between them.

To confirm this effect, the researchers then injected certain antibodies against beta-amyloid protein fragments. These latched onto and inactivated the dimers, preventing their toxic effects in the animal models. However, much work remains to be done before inactivation of dimers could move into the clinic.

"Scientists have theorized for many years that soluble beta-amyloid may be critical to the development and progression of this devastating disease. Now these researchers have isolated a candidate causative agent from brains of people with typical Alzheimer's and directly tested it in an animal model," said Richard J. Hodes, M.D., Director of the National Institute on Aging(NIA), which financed the research. "While more research is needed to replicate and extend these findings," Hodes said, "this study has put yet one more piece into place in the puzzle that is Alzheimer's."

The animal findings were consistent with what the researchers found when they examined the brain tissues of people who had been clinically diagnosed with Alzheimer's and those without dementia. They detected soluble dimers and some trimers of amyloid in the brains of patients with Alzheimer's, but none or very low levels in those free of the disorder. Some people free of the disorder, however, did have insoluble amyloid plaques in their brains.

"These findings may help explain why people with normal cognitive function are sometimes found to have large amounts of amyloid plaques in their brains, which has been a puzzle for some time," said Marcelle Morrison-Bogorad, director of the NIA Division of Neuroscience. "Their findings noted that the brain of an individual who was never clinically diagnosed with dementia was found with abundant insoluble Alzheimer's plaques, but no soluble beta-amyloid."

Selkoe and Shankar noted that further insights into the early stages of this disease process may answer questions not only about Alzheimer's, but also about age-related memory impairments. "The approaches we used to isolate dimers and the widespread availability of tissues from brain banks, open new avenues of investigation into how these aggregates induce Alzheimer's disease," said Selkoe. "We still need to find out why dimers in particular are so destructive to neurons."

SOURCE : Harvard University