Journal of Neuropathology and Experimental
Neurology: Vol. 60, No. 12, pp. 1198–1207.
Raymond A. Sobel, MD, Azam S. Ahmed,
AB
Department of Pathology (RAS), Stanford
University School of Medicine, Stanford, California and
Veterans Affairs Health Care System,
Palo Alto, California;
Loyola University, Stritch School
of Medicine (ASA), Maywood, Illinois.
Abstract
Extracellular matrix (ECM) alterations
in the central nervous system (CNS) of multiple sclerosis (MS) patients
result from blood-brain barrier breakdown, release and activation of proteases,
and synthesis of ECM components.
To elucidate their potential pathophysiologic
roles, we analyzed expression of major CNS ECM proteoglycans (PGs) in MS
and control CNS tissues.
In active MS plaque edges, 3 CNS
lecticans (versican, aggrecan, and neurocan) and dermatan sulfate PG were
increased in association with astrocytosis; in active plaque centers they
were decreased in the ECM and accumulated in foamy macrophages, suggesting
that these ECM PGs are injured and phagocytosed along with myelin.
In inactive lesions they were diminished
and in normal-appearing white matter they showed heretofore-unappreciated
abnormal heterogeneous aggregation.
Phosphacan, an ECM PG abundant in
both gray and white matter, was less markedly altered.
Since in development the spaciotemporal
expression of ECM PGs influences neurite outgrowth, cell migration, axon
guidance, and myelination, these data suggest that
1) enhanced white matter lectican
and dermatan sulfate PG expression in the pro-inflammatory milieu of expanding
lesion edges contributes to their sharp boundaries and the failure of neuronal
ingrowth;
2) decreases in plaque centers may
preclude regeneration and repair; and
3) diffuse ECM PG damage relates
to axon degeneration outside of overt lesions.
Thus, ECM PG alterations are specific,
temporally dynamic, and widespread in MS patients and may play critical
roles in lesion pathogenesis and CNS dysfunction.
© Copyright by American Association
of Neuropathologists, Inc. 2001