Alzheimer's Dementia Cause Clarified
More than a century has passed since Alois Alzheimer first identified abnormal plaques and tangles in the brain of a woman with dementia. Though much has been learned since then, treatments for Alzheimer’s disease remain largely ineffective and diagnostics inadequate. New work from a collaboration led by HMS professor Dennis Selkoe and his lab, however, may help change that.
Using extracts directly from human brain tissue, Selkoe, the Vincent and Stella Coates professor of neurologic diseases in the Department of Neurology at Brigham and Women’s Hospital, and his colleagues found that dimers of human amyloid-beta protein (Abeta), the smallest possible assembly of the peptide, can induce the synapse dysfunction and loss that are hallmarks of early-stage Alzheimer’s. The study, published online in Nature Medicine on June 22, provides insight into how the disease begins in the human brain and how it might be treated.
This work is a refinement of the hypothesis that excess Abeta initiates Alzheimer’s disease, said Selkoe, who helped propose it in 1991. “All forms of Abeta are bad news. You don’t want it to build up. But smaller assemblies”—the very first assemblies to form when the body produces excess Abeta—“are worse.”
The results are compelling because over the past decade much of the evidence supporting this hypothesis has relied on model experimental systems that use synthesized forms of Abeta or Abeta produced from cell cultures. “That’s fine. It’s useful. It’s easy,” said Selkoe, whose lab first reported that cultured cells produce Abeta, which can be used for research purposes. “But why don’t we go right to the source?”
Selkoe and first author Ganesh Shankar, now a third-year MD student at HMS, did just that by starting with donated brain specimens from recently deceased patients with a variety of types of dementia. Shankar extracted material from these brains and found substantial amounts of soluble Abeta in the Alzheimer’s brains and little in the others.
Soluble Abeta oligomers may float freely inside the brain’s extracellular fluid spaces. Over time, these soluble complexes clump together into insoluble fibrils that are deposited as amyloid plaques. Since previous research had shown that soluble Abeta levels correlate most strongly with cognitive symptoms in Alzheimer’s disease, Shankar, Selkoe, and collaborators focused their efforts on it first.
Shankar and Shaomin Li, HMS instructor in neurology at BWH, found that soluble Abeta extracted directly from human cortex potent-ly inhibited long-term potentiation, a key neural mechanism for forming new memories, in the hippocampus of normal mice. Soluble Abeta also facilitated long-term synaptic depression, essentially priming hippocampal neurons to tune some signals out.
To test the physiological effects of soluble human Abeta on the synapse, Shankar and Selkoe connected with Bernardo Sabatini, HMS associate professor of neurobiology. In 2007, Sabatini had worked with Shankar, then an HMS PhD candidate, on a Journal of Neuroscience paper showing that soluble Abeta secreted by cultured cells disrupts synaptic spines. In the new work, Shankar and Sabatini repeated those experiments, this time using soluble Abeta oligomers from Alzheimer’s brains. Again, they observed synapse loss, which is the strongest neuropathological correlate of Alzheimer-type dementia.
Their analysis implicated the same mechanism observed in their 2007 work. Though still incompletely understood, the human Abeta oligomers appear to be “pathologically activating a normal pathway, biasing it toward this synapse loss,” said Sabatini.
The team then collaborated with researchers at University College Dublin to test the human peptide’s effect on behavior. The scientists injected into the brains of rats trained to avoid a dark chamber either a sample containing soluble human Abeta or a sample from which the Abeta had been removed. The soluble form “made the rats forget and go back into the dark chamber as if they had never been trained before,” said Shankar.
The group then turned from free-floating Abeta assemblies in the brain to the largely insoluble amyloid plaques, also extracted from human brains with Alzheimer’s disease. “A major conundrum in the Alzheimer field has been whether amyloid plaques are bad or good,” said Selkoe. “The answer, almost certainly, is both.”
On the good side, he said, “We found that the isolated plaques were largely without biological activity” on synapses. They seem to act as reservoirs that collect smaller amyloid assemblies and sequester them, thereby keeping toxic Abeta oligomers out of circulation. This suggests that plaques, though they may have some pathologic effects, are not principally involved in initiating the early synaptic impairments in Alzheimer’s disease.
However, Selkoe believes that the plaques appear to have a “maximum capacity.” Once that capacity is reached, excess free-floating assemblies, including toxic soluble dimers, have nowhere to go, leaving them free to “diffuse into synaptic clefts and cause injury,” he explained.