A NEURONAL ANTIGEN IN THE BRAINS OF ALZHEIMER PATIENTS

Abstract

The material presented herein describes the production and study of a monoclonal antibody, Alz-50, that recognizes an antigen, A68, which accumulates in the brains of individuals who have Alzheimer's desease. Alz-50 was 50 times more reactive with brain tissue from individuals who died with Alzheimer's Disease than from individuals who were free of neurologic disease at the time of death. Though a western blot of crude brain homogenate revealed no reactivity, partial purification of the antigen on a sephacryl S-400 column revealed immunoreactivity detectable by ELISA eluting at the void volume. Upon western blot analysis, Alz-50 recognized a protein of apparent molecular weight 68,000 D, named A68, that was present in samples from Alzheimer brain but absent from normal brain. A68 was also not detectable by ELISA or western blotting in tissue from individuals who died with neurologic disease that does not exhibit neurofibrillary pathology. Only trace amounts of A68 were detectable in brain tissue from individuals who died with neurologic diseases that exhibit neurofibrillary pathology, such as cases of Guam-Parkinson Dementia Complex and Pick's Disease. In Alzheimer brain, immunocytochemistry revealed that A68 is present in neurons, neuritic plaques and in neurites. Ultrastructural analysis using immunogold labelling demonstrated that A68 can be found associated with isolated filaments in the cytoplasm and with bundles of paired helical filaments. In diseases exhibiting neurofibrillary pathology A68 is restricted to the cell bodies of affected neurons. An immediate application of the selective accumulation of A68 in Alzheimer's disease is for diagnosis. To this end, a method for detecting A68 in cerebrospinal fluid has been developed.;In normal human physiology, A68 is a developmentally controlled antigen present in neurologically normal fetuses and infants. By 6 years of age, expression of A68 is reduced 20 fold and is undetectable in normal adults. However, in the brains of Alzheimer and Down's patients, A68 is re-expressed at a level greater than that seen during development.