Breakdown Of Myelin Implicated In Alzheimer's

Myelination continues sheathing axons until we reach the age of about 50, but in these later stages, the myelin becomes more and more susceptible to damage. Now, in a report in the April issue of the journal Alzheimer's & Dementia, Dr. George Bartzokis, UCLA professor of neurology, suggests that it is the breakdown of this late-stage myelin that promotes the buildup of toxic amyloid-beta fibrils that eventually deposit in the brain and become the plaques which have long been associated with Alzheimer's disease.

These amyloid products in turn destroy more and more myelin, according to Bartzokis, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer's. If correct, the research suggests a broader approach to therapeutic interventions for the disease.

And in a unique twist for modern-day science, Bartzokis tested his myelin model of Alzheimer's by comparing modern imaging results with maps of cortical myelination that were published in the medical journal The Lancet — back in 1901.

"Myelination is the single most unique aspect in which the human brain differs from those of other species," said Bartzokis, who also directs the UCLA Memory Disorders and Alzheimer's Disease Clinic. Myelin is produced by oligodendrocytes, specialized glial cells that themselves become more vulnerable with age.

"Myelination of the brain follows an inverted U-shaped trajectory, growing strongly until middle age. Then it begins to breakdown," Bartzokis said. "Before the advent of modern medicine, very few persons lived beyond age 50 and therefore, as a species, we evolved to continue myelinating over our entire natural life span."

As a result, the volume of myelinated white matter increases to a peak at about age 50, then slowly begins to reverse and decline in volume as we continue to age. The myelin that is deposited in adulthood ensheaths increasing numbers of axons with smaller axon diameters, and so spreads itself thinner and thinner, he said. As a result, it becomes more susceptible to the ravages of age in the form of environmental and genetic insults and slowly begins to break down.

"The myelin breakdown process mimics the developmental process of myelination, but this time in reverse," Bartzokis said. "That's what we think underlies the progressive spread of the neuritic plaques from the late-myelinating regions toward the earlier-myelinating regions."

Bartzokis noted that a similar progression has been described clinically of the cognitive, functional and neurologic declines that accompany Alzheimer's disease.

Oligodendrocytes and myelin have the highest levels of iron of any brain cells, Bartzokis said, and circumstantial evidence supports the possibility that brain iron levels might be a risk factor for age-related neurodegenerative diseases like Alzheimer's. In the study, he suggests that myelin breakdown in the late-myelinating regions releases iron, which promotes the development of the toxic amyloid oligomers and plaques, which in turn destroy more myelin.

Bartzokis tested his hypothesis by examining published images of amyloid deposition acquired in living individuals; the images were made using radiolabeled ligands, molecules that bind to amyloid plaques in the brains of Alzheimer's patients. Next, he compared the physical location of these plaques to much earlier work published in a 1901 edition of The Lancet that mapped the locations in the brain where late-stage myelination occurs. The two matched up perfectly.

"It was pretty striking," Bartzokis said. "And the results are easily testable using currently available imaging methods. What's important is that these results have implications for novel therapeutic interventions that could target oligodendrocytes, myelin and iron deposits in the brain."

The research was funded by the National Institute of Mental Health, the National Institute on Aging, and the Psychiatry Services of the Department of Veterans Affairs. Po Lu, an assistant clinical professor in the UCLA Department of Neurology, and Jim Mintz, professor of psychiatry at the David Geffen School of Medicine at UCLA, were co-authors on the study.