11 Nov 1998

The regulation of neuronal plasticity and regeneration in the CNS is an aspect of Alzheimer’s disease that often has to compete with the big stars, such as amyloid or presenilin, for attention. Yet, it is clear that understanding the factors that regulate axonal growth and the formation and maintenance of connections between neurons is an important part of any approach to AD and other neurodegenerative diseases. The study of axonal regeneration is largely the purview of investigators who do not necessarily have neurodegenerative diseases in mind. Yet the approaches taken, and the biological questions asked, are often related.

A good example of this was provided in the symposium talk given by Dr. Jerry Silver of Case Western Reserve University, Cleveland, who has made a number of contributions to the study of factors involved in promoting, or inhibiting, regrowth of axons in the mature mammalian CNS. His presentation focused on work carried out over the past couple years in which the potential for regeneration within the mature mammalian brain has been dramatically demonstrated through the use of microtransplants of dorsal root ganglion neurons into major white matter fibers tracts (e.g., the corpus callosum) of the mature rat brain. Long-distance regeneration, extending for up to several millimeters, was found in those cases where there was no evidence of glial activation in the area of the transplant. Conversely, regenerating axons stopped when encountering zones of increased expression of chondroitin sulfate. In a search for stimuli that might serve to activate astrocytes, one of the most effective agents was found to be amyloid. In fact, astrocytes cultured on amyloid spots reacted by producing a complex substrate that included chondroitin sulfate—a substrate that was hostile to neurons subsequently cultured on the same spots. Enzymatic digestion of the chondroitin sulfate neutralized the hostile substrate. The amyloid spots without astrocytes were also otherwise permissive for neuronal growth. In light of the demonstrated presence of proteoglycans in plaques, these results suggest that similar phenomena may underlie some of the neuritic pathology in AD.

Although the focus of Dr. Silver’s talk was on the relevance of these findings to the promotion of long-distance axonal regeneration in the injured mammalian spinal cord, a dramatic result that will certainly stimulate renewed optimism for the eventual restoration of function following spinal cord injury, the same principles may have direct relevance to understanding the local regulation of neurite growth in the vicinity of the AD plaque. It is this type of synergy across disciplines and models that represents some of the most abundant fruit to be harvested from an interdisciplinary approach to the study of neuroscience.—Keith A.Crutcher