Sci. Aging Knowl. Environ., 9 March 2005
Vol. 2005, Issue 10, p. nf19
[DOI: 10.1126/sageke.2005.10.nf19]


Early Warning

Memory fades when {beta} amyloid accumulates inside neurons

R. John Davenport

Garbage outside a restaurant can attract rats, but a sloppy kitchen inside might be riskier for diners. Similarly, new work shows that mice suffer memory loss when an Alzheimer's disease (AD) protein accumulates in their neurons, before they develop plaques outside brain cells. The finding bolsters the idea that intracellular protein buildup, rather than extracellular clumping, instigates the disease.

The brains of AD patients are riddled with plaques of {beta}-amyloid protein, which has led researchers to posit that the globs kill neurons and sap memory. But the number of plaques doesn't jibe with the severity of memory problems, so scientists have looked for other triggers. {beta} amyloid also accrues inside neurons, and some researchers blame this throng for disrupting the brain's workings. Two years ago, neurobiologist Frank LaFerla of the University of California (UC), Irvine, and colleagues studied a mouse line that accumulates intracellular {beta} amyloid and found that their neurons don't transmit signals properly. Now, the team has assessed mental prowess in these animals.

The researchers gave the mice two memory tests. In the first, they assessed how quickly rodents swam to a hidden platform in a tank of water, a measure of the animals' capacity for learning and remembering spatial orientation. In the second, they placed rodents in a bright chamber connected to a dark one. When the mice scuttled to the dark side to avoid the light, they received a shock. Subsequent trials determined how long they stayed on the bright side, reflecting their memory of the shock. Two-month-old mutant mice, which don't harbor {beta} amyloid, performed as well as normal mice on both tests. At 6 months of age, the mutant animals displayed plaques and intraneuronal {beta} amyloid. They took longer than normal to learn each task. Moreover, their performance 90 minutes and 1 day after training was substandard, suggesting that they lost short- and long-term memory.

At 4 months of age, mice carried intraneuronal {beta} amyloid but not plaques. They learned the tasks as quickly as did normal animals and retained short-term memory. But their long-term memory faltered; 24 hours after training, they took twice as long to find the hidden platform as did normal animals. Injecting 4-month-old animals with a {beta}-amyloid-grabbing antibody removed the protein from the hippocampus, a brain region required for the tank test. But {beta} amyloid remained in the amygdala, a zone used during the shock test. Treated animals performed well on the former test but not the latter. "Intraneuronal [{beta} amyloid] appears to be the triggering factor in cognitive decline," concludes study co-author Lauren Billings of UC Irvine. If you're looking at plaques, "you're looking too late."

The new work provides "powerful evidence" that intracellular {beta} amyloid instigates memory loss, says neurobiologist Gunnar Gouras of Weill Medical College of Cornell University in New York City. However, he notes that the animals used in the study stash more {beta} amyloid inside their neurons than do other rodent models of AD or human AD patients, which might exaggerate the molecule's importance. Further studies should help clarify whether AD results from bad housekeeping inside brain cells.

March 9, 2005
  1. L. M. Billings, S. Oddo, K. N. Green, J. L. McGaugh, F. M. LaFerla, Intraneuronal A{beta} causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 45, 675-688 (2005). doi:10.1016/j.neuron.2005.01.040 [CrossRef][Medline]
Citation: R. J. Davenport, Early Warning. Sci. Aging Knowl. Environ. 2005 (10), nf19 (2005).

Science of Aging Knowledge Environment. ISSN 1539-6150