AMYLOID REPRIEVE

AMYLOID REPRIEVE:Courtesy of the National Institute on AgingAmyloid β is the cleavage product of Amyloid Precursor Protein (APP). Long suspected a culpable player in Alzheimer disease progression due to the plaques it forms, Aβ may have a physiological role depressing neuronal function.Recent work has revealed a potential physiological role for amyloid β, often considered a major culprit in Alzheimer disease (AD) pathology. This suggests that Aβ, an ordinarily upstanding prot

Jill Adams
Mar 28, 2004
<p>AMYLOID REPRIEVE:</p>

Courtesy of the National Institute on Aging

Amyloid β is the cleavage product of Amyloid Precursor Protein (APP). Long suspected a culpable player in Alzheimer disease progression due to the plaques it forms, Aβ may have a physiological role depressing neuronal function.

Recent work has revealed a potential physiological role for amyloid β, often considered a major culprit in Alzheimer disease (AD) pathology. This suggests that Aβ, an ordinarily upstanding protein, turns bad as the result of a mob-type effect, when the physical buildup into plaques promotes neuronal damage and loss. "There's been a growing awareness over the last three or four years that it's not just a toxic peptide," says Hugh Pearson from the University of Leeds, UK.

Pearson used specific enzyme inhibitors to block β- and γ-secretase, which produce Aβ through the sequential cleavage of amyloid precursor protein (APP).1 Death occurred in neuronal cell lines...

FLAGGING THE EVIDENCE

By no means is it clear that either of these findings represents true functions of Aβ in normal brain, Malinow cautions. "We can kind of wave our hands and say there's some evidence." Yet the buzz in the AD research community reflects the sense that the identified effects are a good fit in the larger scheme of neurobiology.

Both studies rely on APP produced endogenously, which provides a significant advantage over previous methods, says José Esteban from the University of Michigan, Ann Arbor. Previous work done with exogenous application showed Aβ effects on ion channels, neurite growth, and cell adhesion. "In neurons, everything is compartmentalized," Esteban says. The risk of adding proteins exogenously is that they may gain access to a compartment where they do not belong.

Pearson set out to study endogenous Aβ in physiologic quantities by using secretase inhibitors. Several experiments were done to rule out nonspecific toxicity of the treatment. Aβ immunostaining was reduced in treated cultures. Antibody neutralization of Aβ mirrored the toxic effect of secretase inhibitors. And adding back exogenous Aβ recovered cell viability. But, how the neurons die remains to be determined, says Pearson.

Secretase inhibitors are being vigorously investigated as potential treatments for AD. "A lot of people have interpreted our paper as saying secretase inhibitors are bad," says Pearson. But he disagrees. The trick, he says, will be to reduce but not abolish Aβ production in AD, in which "there's a greater amyloid load."

SYNAPTIC FUNCTION

While neurons do die in later stages of AD, symptoms of dementia occur before significant plaque buildup and cell loss are evident. For this reason, some have suggested that Alzheimer is a disease of synaptic failure rather than neuronal death.

To study synapses, Malinow used hippocampal slices in which neuronal circuitry is maintained, and he discovered Aβ 's negative feedback function. Neuronal activity increased Aβ production by inducing β secretase. The ensuing synaptic depression was pharmacologically dissected to reveal Aβ as the responsible molecule.

Lauded for its rigorous combination of genetics, pharmacology, and electrophysiology, the Malinow study has its limitations, specifically the use of overexpressed human APP. Over-expression can result in "massive concentrations" of APP and Aβ, says Pearson. Moreover, Esteban adds, using human-type APP in rat tissue introduces an artificial component. Malinow says that testing the effects of endogenous rat Aβ resulted in data "consistent with" the overexpression system, but the quantities were too small to analyze, and the results were not included in the paper.

Malinow's study is one of the "first and best so far to pinpoint what Aβ might do in terms of synaptic function," says Denis Selkoe at Harvard's Brigham and Women's Hospital. "Disruption of this feedback system could contribute to disease progression in Alzheimer disease, because Aβ gets tied up with aggregation."

Maybe Aβ doesn't turn bad, but gets "taken out of action," says John Trojanowski, director of the Institute on Aging at the University of Pennsylvania. The discovery of whether disease results from a "toxic gain in function or through a loss in function" depends on the scientific pursuit of the normal function and regulation of Aβ, he says, and will open up new avenues for therapeutic intervention.

Jill U. Adams juadams@verizon.net a freelance writer in Albany, NY.

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