Contribution of changes in ubiquitin and myelin basic protein to age-related cognitive decline

Abstract

The structural substrates for age-associated cognitive and motor slowing are not known, but age-related white matter changes, such as ubiquitin (UBQ)-immunoreactive granular degeneration of myelin, might contribute to this slowing. To address this hypothesis we measured immunoreactivity for UBQ and myelin basic protein (MBP) in frontal white matter of age-, sex- and postmortem interval-matched cases with no cognitive impairment (NCI; N=12), mild cognitive impairment (MCI; N=14) and Alzheimer disease (AD; N=12). There were no significant correlations between UBQ in white matter and cognitive measures, but MBP was significantly lower in AD compared with NCI and MCI. MBP correlated with overall cognition as assessed by neuropsychological summary scores, as well as with timed cognitive tests and those that reflect frontal functions. An age-related decrease in MBP immunoreactivity was detected in NCI cases (r=0.71). These results support the hypothesis that white matter pathology may contribute to age-associated decline in cognition.

Introduction

Myelin pathology is a common feature of aging and is also seen in age-related degenerative diseases. A common form of myelin pathology in aging is granular degeneration of myelin. Granular degeneration of myelin was first observed at the ultrastructural level by Terry et al. (1964) in biopsies of Alzheimer’s disease (AD) and was further characterized by Rees in normal brain biopsies (Rees, 1976). Structurally, it is characterized by expansions within the myelin sheath that contain heterogeneous, dense and amorphous material. The extent of granular degeneration of myelin was only realized with the advent of ubiquitin (UBQ) immunocytochemistry (Dickson et al., 1990). Granular degeneration of white matter is almost universal in elderly brains, but uncommon in young brains (Dickson et al., 1990, Pappolla et al., 1989). Developmentally, ubiquitin-immunoreactive granular degeneration of myelin is detected as early as the third decade of life (Dickson et al., 1990). No concerted effort has been made to rigorously and objectively measure the amount of ubiquitin-immunoreactivity in white matter as a function of age. Nor has there been any attempt to correlate this observation with indices of motor and mental impairment.

Ubiquitin is a member of the family of low molecular weight (∼8.5 kDa) heat shock proteins that serves a vital role in physiologic and pathologic protein turnover (Ciechanover et al., 2000). Cell stress mediated by oxidative mechanisms is common in aging (Stadtman, 1992), and is often associated with protein denaturation, which is subject to proteolysis. In a variety of different tissue types, high molecular weight (>60 kDa) ubiquitin conjugates progressively increase with age (Goto et al., 2001). Age-related increases in ubiquitin conjugation may be a response to age-related protein damage. The proteins to be degraded by this system are covalently modified by ubiquitin and eventually targeted for degradation via either proteasomes or lysosomes (Ciechanover et al., 2000). Of particular interest is the fact that ubiquitin is associated with a number of cytological alterations in aging and in degenerative disorders (Lowe et al., 1988). Moreover, ubiquitin immunoreactivity is increased in cortical gray matter in AD, presumably due to the presence of ubiquitin in neurofibrillary tangles and neuritic plaques (Wang et al., 1991; Wang et al., 2001a, Wang et al., 2001b; Mori et al., 1987).

Myelin disorders of all types are known to be associated with slowing of nerve conduction velocity. The major structural protein of myelin is myelin basic protein (MBP), which is a family of proteins consisting of multiple polypeptide chains varying in molecular weight from 14 to 21.5 kDa (Givogri et al., 2000). At least four isoforms of MBP have been identified in humans (Kamholz et al., 1986). The gene encoding MBP has been mapped to chromosome 18 (Sparkes et al., 1987). Although the function of MBP is still largely unknown, it is thought to play an important role in compaction of the myelin sheath. Given widespread alteration of myelin in the aged brain, we hypothesized that changes in MBP would correlate with measures of motor and mental slowing that are virtually inevitable with aging.

In the present study, ubiquitin and MBP immunoreactivities were measured in frontal white matter of subjects participating in the Religious Orders Study, a longitudinal clinicopathologic study, including subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI) and clinically probable AD. To explore the possible associations of changes in ubiquitin and MBP on cognition, the relationship of ubiquitin and MBP to various clinical and neuropsychological variables was analyzed.