ADDLs: a new explanation for Alzheimer disease.

Clumps of large, sticky proteins forming senile plaques have been observed in the brains of people with Alzheimer disease ever since neurologist Alois Alzheimer first described the disorder nearly a century ago. However, only in the last few years have researchers begun to understand how the primary component of these proteins, a compound known as [beta]-amyloid (A[beta]), disables and kills brain cells. Recent work shows that other forms of A[beta] known as A[beta]-derived diffusible ligands, or ADDLs, may, along with senile plaques, play a key role in the pathogenicity of Alzheimer disease. True to the promise of environmental medicine, these findings could contribute to better methods for diagnosing Alzheimer disease, as well as new therapies to halt its progress.

Recent research by postdoctoral fellow Yuesong Gong, neurobiology and physiology professor William Klein, and other researchers at Northwestern University, published in the 2 September 2003 Proceedings of the National Academy of Sciences, shows that ADDLs bind to synapses, connection points that allow the exchange of signals between neurons. There they disrupt the signaling needed to form memories, says Klein, a member of the Northwestern Cognitive Neurology, and Alzheimer's Disease Center.

A[beta] is formed by the breakdown of the amyloid precursor protein, a molecule of unknown function that is embedded in the membrane of some cells. It is not unusual for cells to make A[beta], but in persons with Alzheimer disease, for reasons that are not yet known, production of A[beta] either dramatically increases or its breakdown decreases. The Northwestern team found up to 70 times as many ADDLs in brain tissue from persons with Alzheimer disease compared to brain tissue from persons without the disease.

Once formed, A[beta] molecules can fold on themselves and bind to each other. Early in this process, they link in globules of 12-24 molecules to form ADDLs. Eventually, in a process described in the 18 April 2003 issue of Science by a team including Carl Cotman, director of the University of California, Irvine, Institute for Brain Aging and Dementia, ADDLs can bind to cells until they begin to appear as diffuse plaques.

In the early 1990s, researchers thought that plaques were the most toxic form of A[beta]. But recent research indicates that ADDLs may be more damaging. Studies in mice have shown that memory loss correlates more strongly with the presence of ADDLs than with the presence of senile plaques, and that treatments to reduce ADDL levels can actually reverse memory loss. "It's very likely that [senile plaques] can be bioactive; they've been seen attached to the sides of nerve cells, but the damage they cause is probably limited," says Klein, who further speculates, "The ADDLs are much more insidious because they diffuse between cells until they find just the right target."

Cotman's team and others have also found that ADDLs are similar in size and shape to prions, molecules that have been linked to the transmission of bovine spongiform encephalopathy ("mad cow disease") and other neurodegenerative diseases. They may therefore share a common mechanism of toxicity.

ADDLs have been measured in cerebrospinal fluid. Measurement of ADDL levels could eventually serve as a diagnosis of Alzheimer disease, especially in its early stages, and could be more accurate than the cognitive evaluations currently used, says Klein. His team is working to see if ADDL levels that correlate to the disease can be detected in less-invasive blood tests.

Recent ADDL discoveries could also contribute to research into potential antiamyloid therapies, which currently fall into three groups: immunotherapies that prompt the body's immune system to destroy A[beta], antiaggregants that keep the molecules from clumping, and enzyme (secretase) modulators that prevent the creation of A[beta] or hasten its destruction. "All three approaches show some efficacy in transgenic animal models," says Samuel Gandy, vice chair of the medical and scientific advisory council of the Alzheimer's Association and director of the Farber Institute for Neurosciences at Thomas Jefferson University.

An immunotherapy approach using vaccine has shown mixed results so far. Although some patients in phase II trials showed cognitive benefits, some 5% also developed acute allergic encephalitis for reasons yet unknown. Klein speculates that a vaccine that focused on A[beta] in ADDL form, as opposed to plaques, could be more effective, cause less inflammation, and require less vaccine. Further, he says, there are no reasons a priori that should prevent development of ADDL-specific therapeutic antibodies, which would constitute a "passive" vaccine. "It's a challenging and exciting approach, but there's a lot of work to go yet," says Cotman.

Several drugs to inhibit A[beta] clumping are in clinical trials, according to Gandy. Enzyme-based therapies could use existing compounds--recent studies indicate that some antioxidants, including vitamin E and curcumin (the main ingredient in curry), may inhibit A[beta] accumulation. Other research has shown that statins (cholesterol-lowering drugs) and estrogen activate a form of secretase that destroys A[beta], says Gandy. There are indications that other lifestyle and environmental factors may also decrease A[beta] levels. For example, some epidemiology studies link exercise with delayed onset of Alzheimer disease, says Cotman. "Ultimately," he says, "we may be looking at a combination of behavior, new drugs, and nutrients to treat Alzheimer's disease."