Faculty Bibliography

Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease (CLD) and abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.

Unlike other infectious diseases, transmissible spongiform encephalopathies elicit no specific immune response. Indeed, because the infectious agent, the prion, seems to be essentially composed of a protein with a primary structure identical to a host encoded protein, the lymphoid system is naturally tolerant. However, lymphoid organs are strongly implicated in the early peripheral steps of the disease. Paradoxically, immunodeficient animals, which are more susceptible to infections by usual pathogens, appear to be partially or completely resistant to experimental infection by prions by peripheral route. Several studies suggest that in normal subjects, cells of the immune system support the replication of prions and might allow their spreading from the periphery to the central nervous system. Thus, the lymphoid system appears to behave as a Trojan horse rather than a protective fortification in the process of prion infection. A greater understanding of the pathophysiology of these aspects of prion diseases could lead to immunomanipulation strategies aimed at preventing prion spread into the central nervous system, once peripheral exposure has occurred

This report examines plasma amyloid beta proteins A beta 40 and A beta 42 and apolipoprotein E (apoE) levels and their relationships with age in non-demented older adults with (N = 32) or without the apoE-epsilon 4 allele (N = 94). A beta levels did not differ between the groups whereas the epsilon 4 allele was associated with a significant reduction in plasma apoE. In subjects with the epsilon 4 allele, increasing age was associated with significant reduction in plasma A beta 40. Subjects without the epsilon 4 allele showed a significant positive correlation between A beta 40 and A beta 42 levels. There was also a significant correlation between plasma A beta 40 and apoE levels in all subjects