Sci. Aging Knowl. Environ., 2 April 2003
Vol. 2003, Issue 13, p. nw51
[DOI: 10.1126/sageke.2003.13.nw51]


Settle Down!

Alzheimer's protein might calm rambunctious neurons

Mitch Leslie;2003/13/nw51

Key Words: NMDA • Sindbis expression system • {beta}-secretase • {gamma}-secretase • {beta}-CTF

Like preschoolers, brain cells need help to curb their natural hyperactivity. A new study suggests that {beta} amyloid prevents neurons from acting up. The protein piles up in Alzheimer's disease (AD), but by identifying a possible beneficial function, the research supports the contention that {beta} amyloid isn't just harmful cellular refuse.

Clots of {beta} amyloid scar the brains of people with Alzheimer's disease (see "Detangling Alzheimer's Disease"). Neuroscientists have battled over whether {beta} amyloid performs a useful job in the brain or is simply garbage. Some studies suggest that it helps control communication between neurons. For example, hiking {beta} amyloid output in mice diminishes signal transmission across synapses in the hippocampus, a brain region necessary for laying down memories. But researchers crank up {beta} amyloid by engineering mice to produce extra {beta}-amyloid precursor protein (APP), a larger molecule from which {beta} amyloid is dissected. Such lifelong exposure to excess APP and {beta} amyloid might alter brain development and mask the biological activity of {beta} amyloid.

To clarify {beta} amyloid's role in modulating neuron signals, Roberto Malinow, a neuroscientist at Cold Spring Harbor Laboratory in New York, and colleagues boosted its production in hippocampus cells from normal rats, using a virus to spirit the gene for human APP into the neurons. This technique allows researchers to rapidly increase amounts of APP and {beta} amyloid instead of elevating them throughout an animal's life. The scientists selected pairs of adjacent neurons and used miniature electrodes to measure one cell's response when the other is stimulated. The jolt evoked a smaller current in cells carrying extra APP than in control cells. Dousing the cells with a compound that curtails the release of {beta} amyloid banishes this effect, suggesting that the protein damps signals that travel between neurons.

The researchers also investigated whether brain activity controls {beta}-amyloid production. They used slices of hippocampus from mice engineered to manufacture human APP. Compounds that stimulate firing of neurons goaded cells to make extra {beta} amyloid; inhibitors of neuron activity slashed release of the protein. The results suggest that {beta} amyloid is part of a control system to rein in cell firing, says Malinow. "Its normal function may be to keep [brain] hyperactivity in check," he says. How excess {beta} amyloid spurs the mental decline seen in AD remains unknown, he says. An overabundance of the protein might squelch signals throughout the brain, causing a "mental brownout." Or by weakening synapses, the protein might promote death of brain cells.

The study is important because it pinpoints a potential normal vocation for {beta} amyloid, says neuroscientist Cui-Wei Xie of the University of California, Los Angeles. AD expert David Cook of the University of Washington, Seattle, agrees: "This paper offers intriguing hints that {beta} amyloid serves a purpose in feedback regulation of neuron activity." Governing neuron firing is vital, he adds, because without the right amount of inhibition, "your brain is wired to go nuts." Further work might reveal just how {beta} amyloid coaxes restless neurons to quiet down.

--Mitch Leslie

April 2, 2003
  1. F. Kamenetz et al., APP processing and synaptic function. Neuron 37, 925-937 (2003). [Abstract] [Full Text] [CrossRef][Medline]
Citation: M. Leslie, Settle Down! Sci. SAGE KE 2003, nw51 (2 April 2003);2003/13/nw51

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