Advertisement

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Biological Chemistry

Two-Path Mechanism

Protective pathways may falter with age, sparking Alzheimer's neurodegeneration

by Stu Borman
August 14, 2006 | A version of this story appeared in Volume 84, Issue 33

Dual Path
[+]Enlarge
Dillin, Kelly,and coworkersdiscovered two neuroprotective pathways that may malfunction in Alzheimer's disease. One disassembles small toxic aggregates of Alzheimer's Aβ1-42-peptide (Aβ), and the other converts the small aggregates into less toxic larger ones.
Dillin, Kelly,and coworkersdiscovered two neuroprotective pathways that may malfunction in Alzheimer's disease. One disassembles small toxic aggregates of Alzheimer's Aβ1-42-peptide (Aβ), and the other converts the small aggregates into less toxic larger ones.

A collaborative team has shown that cell damage from protein aggregation in Alzheimer's disease can be greatly reduced by experimentally slowing the appearance of signs of aging and has revealed a dual-pathway mechanism by which this effect may occur.

[+]Enlarge
Credit: Salk Institute
Dillin
Credit: Salk Institute
Dillin
[+]Enlarge
Credit: Scripps Research Institute
Kelly
Camera:   DCS660C
Serial #: K660C-01358
Width:    2008
Height:   3040
Date:  3/17/90
Time:   5:43:49
DCS6XX Image
FW Ver:   3.2.3
TIFF Image
Look:   Product
Sharpening Requested:Yes (Preferences)
Counter:    [21510]
Shutter:  1/30
Aperture:  f10
ISO Speed:  80
Max Aperture:  f2.8
Min Aperture:  f22
Focal Length:  112
Exposure Mode:  Manual (M)
Meter Mode:  Color Matrix
Drive Mode:  Single
Focus Mode:  Manual (AF-M)
Focus Point:  Right
Flash Mode:  Normal Sync
Compensation:  +0.0
Flash Compensation:  +0.0
Self Timer Time:  10s
White balance: Preset (Flash)
Time: 05:43:49.395
Credit: Scripps Research Institute
Kelly

Other groups had shown before that retarding the hallmarks of aging protects against neuronal toxicity associated with a related condition, Huntington's disease, but they didn't demonstrate the mechanism. The new study identifies two previously unknown neuroprotective pathways that may work increasingly less well as organisms age, helping to explain the close association between aging and Alzheimer's at a molecular level.

One pathway disassembles protein aggregates so they can't harm cells. The second, which likely is activated when the first is overtaxed, protects cells by converting small toxic aggregates into less toxic larger ones, perhaps so they can be stored until they can be disposed of properly. The pathways should reveal molecular targets to which future Alzheimer's medications can be directed.

The study was carried out by professor of molecular and cell biology Andrew Dillin of Salk Institute for Biological Studies, La Jolla, Calif.; chemistry professor Jeffery W. Kelly of Scripps Research Institute; and coworkers (Science, DOI: 10.1126/science.1124646). In a worm model of Alzheimer's, they identified the two pathways by using RNA interference to manipulate the expression of transcription factors that control lifespan and by using kinetic assays to monitor protein aggregation.

The preferred pathway breaks down Alzheimer's Aβ1-42-peptide (Aβ) oligomers or small aggregates. "The need for this pathway to be turned on is continual," says D. Stephen Snyder, a specialist in causes of Alzheimer's at the National Institute on Aging, Bethesda, Md. "A by-product is being created, and it has to be escorted out of the cell and disposed of." When that pathway gets overwhelmed, the second pathway forms larger, less toxic Aβ1-42 aggregates, presumably so the main pathway can catch up.

Dillin, Kelly, and coworkers "have pulled together extant threads from other studies into a cogent hypothesis that lends itself to further testing in higher organisms," Snyder says. "The work shows that these pathways exist and to what extent they're used by the cell, and it points to therapeutics. It's a pretty important finding for the field."

Chemistry professor Christopher M. Dobson of the University of Cambridge, in England, says the study "represents an extremely important advance in our understanding of Alzheimer's at a molecular level and, more generally, of all the neurodegenerative disorders linked to protein misfolding and aggregation. It marks a beginning of the crucial process of discovering the underlying reason for one of the most characteristic features of these disorders-that they are unmistakably linked to the aging process."

The work "provides important evidence to support the increasingly popular idea that the true culprits in Alzheimer's are the small aggregates that precede the large fibrils and plaques usually observed in the brains of patients," Dobson says. "It also presents strong evidence that diseases such as Alzheimer's result from the failure of mechanisms that normally protect against the inherent tendency of proteins to misfold and aggregate."

Next step? Dillin and Kelly are trying to better understand the macromolecules that mediate aggregation and disaggregation. They're also pursuing small molecules that will delay aging and deter aggregation-induced neurotoxicity, and they already have some promising hits.

Article:

This article has been sent to the following recipient:

0 /1 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.