Amyloid plaque in the brain
The August 10th issue of the journal Science highlights work that according to the Alzheimer's Association's Sam Gandy, represents the first time that a molecular-level theory has been proposed that might offer a genetic solution to the problem of amyloid plaque formation in the brain.
As the brain ages, the genes HSF-1 and DAF-16 respectively destroy toxic proteins in the cells in the first case and, acting as a sanitary engineer in the second case, remove harmful tangle accumulations.
It is believed that as the brain ages the mechanism governing these genes can malfunction, leading to decline of self-regulation and abnormal accumulations of plaque and Alzheimer's disease. Other genetic factors affect predisposition, including particularly the homogenous zygote APOEe4 genetic marker, which is involved in a high percentage of early onset cases. [Note: In Stanford research, the symbol reversal test was 94% effective in identifying cognitive performance issues in asymptomatic individuals who possessed the above genetic marker]
"Something in the aging process is let loose . . . and this (finding) looks really promising because it leads to a very early event of Alzheimer's," researcher Andrew Dillin of the Salk Institure in San Diego said of the gene discoveries.
The researchers concluded that it's inside the cells where beta amyloid proteins drive the onset of Alzheimer's, and that keeping the HSF-1 gene active will be critical to stopping the disease before it gets started.
"That gives us one molecular link," Dillin said. "If we can detect that in very early Alzheimer's patients, then we can say, 'Ah, you may get it so you need to start taking drug x, y and z.' "
Co-author Jeffery Kelly said he developed new technology that can detect the formation of toxic proteins at sensitivities 1,000 times greater than current techniques.
"If we could detect very small amounts of these things, very early on, then we do have a good window to start preventive treatment – if one existed," Dillin said.
The search for Alzheimer's genes has shifted attention away from aging processes as a cause, but the new study points back at aging, said Dr. Sam Gandy, chairman of the medical and advisory council of the Alzheimer's Association.
The researchers made their discoveries studying a roundworm called c elegans – a widely used animal model because it has several of the same genes as humans. They plan to replicate their findings in mice.
Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer disease (AD) which is associated with the misassembly of the A1-42 peptide. Aggregation-mediated A1-42 toxicity was reduced in C. elegans when aging was slowed by decreased insulin/insulin growth factor (IGF)-1-like signaling (IIS). The downstream transcription factors, heat shock factor-1 (HSF-1) and DAF-16 regulate opposing disaggregation and aggregation activities to promote cellular survival in response to constitutive toxic protein aggregation. Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity.