Autoimmunity to cholinergic‐specific antigens of the brain in senile dementia of the Alzheimer's type

Abstract

AbstractSenile dementia is a common and devastating disease of the elderly. The most common type of senile dementia is Alzheimerapos;s type (SDAT). The cause of SDAT is unknown. Considerable evidence indicates that the basal forebrain cholinergic system of the brain is primarily involved in the disease process. The mechanisms which account for this specificity of injury is unknown. Several lines of evidence have suggested that autoimmunity may play a role in SDAT. In particular, the presence of antibrain antibodies in the sera of patients with SDAT has been described. However, their specificity has not been defined. Our hypothesis proposes that cholinergic‐specific autoimmunity might play a role in the immunopathogenesis of SDAT. We previously presented data to suggest that antibrain antibodies in SDAT sera are directed against cholinergic‐specific brain antigens. In the current study, a synaptosomal lysis assay was employed to determine if SDAT sera caused specific complement‐dependent immunolysis of cholinergic synaptosomes. Immunolysis was determined by the release of choline acetyltransferase (ChAT), glutamate decarboxylase (GAD), dopamine‐beta‐hydroxylase (DBH), lactate dehydrogenase (LDH), and the inhibition of high affinity choline uptake. Sera from two (American and Swedish) groups of SDAT patients and controls were pair‐tested in a blinded fashion on a single batch of synaptosomes. The results demonstrated that both groups of SDAT sera caused significant specific immunolysis of cholinergic synaptosomes. ChAT release, LDH release, and inhibition of choline uptake were caused by SDAT sera in the presence of complement, while control sera showed little effect. No effect was noted on GAD or DBH release. These data support the hypothesis that a cholinergic‐specific autoimmune response may play a role in the immunopathogenesis of SDAT. Further studies are needed to define the immunochemistry of the cholinergic‐specific antigens recognized by SDAT sera.