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Double Trouble
Two-unit peptides may flag early-stage Alzheimer’s disease
by Elizabeth Dougherty

Although much has been learned since Alois Alzheimer first identified abnormal plaques and tangles in the brain of a woman with dementia, treatments for Alzheimer’s disease remain largely ineffective and diagnostics inadequate. New research from a collaboration led by an HMS professor may help address these shortcomings.

Using extracts from human brain tissue, Dennis Selkoe, the Vincent and Stella Coates Professor of Neurologic Diseases in the Department of Neurology at Brigham and Women’s Hospital, and colleagues showed that a two-unit peptide of human amyloid-beta protein (Aβ) can induce the synapse dysfunction and loss that are hallmarks of early-stage Alzheimer’s. This dimer is the smallest configuration possible for the protein. The study, published in the August issue of Nature Medicine, provides insight into how the disease begins in the human brain and how it might be treated.

“All forms of Aβ are bad news,” says Selkoe. “You don’t want it to build up. But smaller assemblies are worse.” Such assemblies are the first ones to form when the body produces excess Aβ.

The results are compelling; until now, evidence of the protein’s involvement in Alzheimer’s came only from model experimental systems in which synthesized forms of Aβ or Aβ produced from cell cultures were used. “That’s fine,” says Selkoe. “But why don’t we go right to the source?”

Source Material

Selkoe and coauthor Ganesh Shankar ’10 did just that by starting with donated brain specimens from deceased patients who had some form of dementia. Shankar extracted material from these brains and found substantial amounts of soluble Aβ in the Alzheimer’s brains, but little in the others.

Soluble Aβ oligomers may float freely inside the brain’s fluid-filled extracellular spaces. Over time, these soluble complexes form insoluble fibrils that are deposited as amyloid plaques. The research team elected to focus on the levels of soluble Aβ. Previous research had shown these levels correlate most strongly with cognitive symptoms in Alzheimer’s disease.

The scientists found that soluble Aβ that was extracted directly from the human cortex was a potent inhibitor of long-term potentiation, a neural mechanism important to the formation of new memories, in the hippocampus of normal mice. Soluble Aβ also facilitated long-term synaptic depression, essentially priming hippocampal neurons to tune some signals out.

Unkind Cuts

To test the effects of soluble human Aβ on the synapse, Shankar and Selkoe connected with Bernardo Sabatini ’95, an HMS associate professor of neurobiology. In 2007, Sabatini and Shankar showed that soluble Aβ from cultured cells disrupted synaptic spines. In this new work, Shankar and Sabatini repeated those experiments using soluble Aβ oligomers from Alzheimer’s brains. Again, they observed synapse loss. According to Sabatini, the human Aβ oligomers appear to be activating a normal pathway and biasing it toward synapse loss.

The team then collaborated with researchers at the University College Dublin to test the human peptide’s effect on behavior. The scientists injected the brains of rats with either a sample of soluble human Aβ or a sample from which the Aβ had been removed. Although the rats in the experiment had previously been trained to avoid a dark chamber, exposure to the soluble form caused the rats to go back into the dark chamber as if they had never been trained.

The group then turned from free-floating Aβ assemblies to the largely insoluble amyloid plaques, also extracted from the brains of humans with Alzheimer’s disease. The researchers found some good news: Isolated plaques generally did not exhibit biological activity on synapses. Instead, they seemed to act as reservoirs that collect and sequester smaller amyloid assemblies, thereby keeping toxic Aβ oligomers out of circulation. This suggests that plaques, though they may have some pathologic effects, are not principally involved in initiating early synaptic impairments in Alzheimer’s disease.

Selkoe believes, however, that plaques have a maximum capacity. Once that capacity is reached, he says, excess free-floating assemblies, including toxic soluble dimers, have nowhere to go and so are free to diffuse into synaptic clefts and cause injury.

Shankar and Selkoe also undertook experiments to chemically isolate Aβ isoforms from the human brains used in the study. They found Ab exists in many different-sized forms. In addition, they found the soluble human Aβ dimer inhibited long-term potentiation while monomers and other higher-order assemblies did not affect this form of synaptic plasticity.

Shankar has tested several potentially therapeutic Aβ antibodies and found that targeting dimers may be effective, with those directed to the peptide’s N-terminus most effective at neutralizing the dimers’ adverse effects. Unpublished results of a trial of a humanized version of the same antibody reported by other researchers also showed positive clinical benefits in certain Alzheimer’s patients in the mild to moderate stages of disease.

Elizabeth Dougherty is a science writer for Focus.

Photo: ©iStockPhoto.com/Joseph Jean Rolland Dube