Cellular Skeleton Collapse May Be Alzheimer’s Precursor
Researchers at the University of California, Santa Barbara, have uncovered a key finding about the process by which the peptide beta amyloid destroys neurons.
Led by Stuart Feinstein, Ph.D., the team at UCSB studied the tau protein, which is present in a neuron’s axons, the long parts that connect with targets. Tau helps stabilize microtubules, a key part of a cell’s “skeletal” structure. While beta amyloid has been understood to have a role in cell death, the exact mechanism that it uses has been unknown.
Dr. Feinstein’s team discovered that beta amyloid did not phosphorylate tau abnormally or excessively, as they expected. Rather, the team observed that beta amyloid completely fragmented tau within one to two hours of the cell’s exposure. Within 24 hours, the cells died. “If you destroy tau, which is an important regulator of the microtubules, one could easily see how that could also cause cell death,” said Dr. Feinstein. “We know from cancer drugs that if you treat cells with drugs that disrupt the cytoskeleton, the cells die. In my mind, the same thing could be happening here.”
The findings were published in the online version of The Journal of Biological Chemistry.
Specific Beta Amyloid Form More Prevalent in Alzheimer’s Brains, Study Finds
A little-understood form of beta amyloid called Abeta43 is more abundant in brains with Alzheimer’s disease and apparently has a greater neurotoxic role in Alzheimer’s than previously known, according to researchers at the RIKEN Brain Science Institute in Tokyo.
Two forms of beta amyloid, Abeta40 and Abeta42, have already been associated with the genetic mutations that cause early-onset Alzheimer’s. Abeta43 is found just as often as Abeta42 in patient brains, but was less thoroughly researched in the past.
The study involved mice with a generated mutation that caused overproduction of Abeta43, and a highly sensitive system that can distinguish between the different types of beta amyloid. They found that Abeta43 is more abundant in the brains of Alzheimer’s patients than Abeta40, and is more neurotoxic than Abeta42. Abeta43 also accelerates amyloid pathology considerably and seems to increase in prevalence with age.
These new findings show that Abeta43 may be a valuable biomarker in Alzheimer’s diagnosis, and could point the way for further study into new approaches for preventing amyloidosis.
The research was published in the journal Nature Neuroscience.
PET Imaging May Help Spot Alzheimer’s Lesions in the Brain
Positron emission tomography (PET), a scanning technology, may help identify lesions associated with Alzheimer’s disease in the brain, according to research published in July.
In one study, a team from the Penn Memory Center in Philadelphia used a tracer called fluorine 18-labeled flutemetamol for brain imaging and conducted PET scans on seven patients. All seven had already undergone a biopsy for normal pressure hydrocephalus, a progressive condition that can be hard to distinguish from Alzheimer’s. The scientists found correspondence between the PET scan readings and the evidence of amyloid lesions, the plaque typically associated with Alzheimer’s, which had been provided by microscopic evaluation of the biopsied tissue. That team was led by David A. Wolk, M.D.
In a second study, a team led by Adam S. Fleisher, M.D., and his team at Banner Alzheimer’s Institute in Phoenix, looked at PET images that used the tracer florbetapir F 18. This study’s population included 68 individuals with probable Alzheimer’s, 60 individuals with mild cognitive impairment, and 82 healthy individuals who functioned as controls. The researchers found differences among the three groups in the brain’s uptake of the tracer, as well as in the detection of amyloid plaque. The differences may be significant enough to help doctors distinguish between conditions, and to detect the difference between impaired brains and their unimpaired counterparts.
Both studies point to possible directions for using PET scans to help identify findings associated with Alzheimer’s. “Biomarkers that provide molecular specificity will likely become of greater importance in the differential diagnosis of cognitive impairment in older adults,” stated Wolk and his team.
Both articles were published in Archives of Neurology.
FDA Eases Rules on Alzheimer’s Clinical Trials
The U.S. Food and Drug Administration (FDA) has loosened safety restrictions on clinical trials for Alzheimer’s drugs, according to new guidelines published in July. The new guidelines allow some patients who develop a brain-swelling condition called vasogenic edema to remain in trials.
The guidelines were published in the journal Alzheimer’s & Dementia. The new rules won’t compromise safety, according to the guidelines’ authors, but will allow more patients who have had brain-swelling events to continue receiving experimental medicines. The old guidelines required that clinical trial patients could have only one incident of cerebral microhemmorhage, which are tiny leaks of blood in the brain, to remain in a study. They also required frequent MRI scans to check for brain swelling or other problems potentially caused by experimental medicines. The study authors point out that many patients have had such events, and excluding them only made it more difficult to find effective treatments for Alzheimer’s.
“Broadening the restrictions would allow a better understanding of the potential risks and benefits of amyloid-lowering treatment,” said Rachel Schindler, a clinical disease expert in Alzheimer’s at Pfizer.
Inherited Alzheimer’s Spotted 20 Years Prior to Dementia
The presence of inherited forms of Alzheimer’s disease may be detected as early as 20 years before symptoms of dementia set in, according to research presented July 20 at the International Conference on Alzheimer’s Disease in Paris.
Many scientists believe that early identification is key to more effective treatment. By the time symptoms become apparent, it is believed, the damage caused by Alzheimer’s is already extensive. “We want to prevent damage and loss of brain cells by intervening early in the disease process—even before outward symptoms are evident, because by then it may be too late,” said Randall Bateman, M.D., of the Washington University School of Medicine in St. Louis and associate director of the Dominantly Inherited Alzheimer’s Network (DIAN), which is an international study of the inherited forms of Alzheimer’s.
The initial results from the DIAN study confirm prior research that suggests that detecting such factors as changes in levels of biological markers in the spinal fluid can predict Alzheimer’s dementia years before symptoms occur. The DIAN researchers are now planning for clinical trials to prevent Alzheimer’s in DIAN study participants.
DIAN is the largest study to date of rare forms of dominantly inherited Alzheimer’s.