ANTINEURONAL ANTIBODIES SIMILAR TO THOSE FOUND IN ALZHEIMERS-DISEASE INDUCE MEMORY DYSFUNCTION IN RATS

Although the etiology and pathogenesis of the cholinergic degeneration in Alzheimer's disease are not known, several reports implicate immunological mechanisms. Recently we have shown that sera of Alzheimer's disease patients contain antibodies which bind specifically to the heavy molecular weight neurofilament protein of Torpedo cholinergic neurons. In the present study we investigated the possibility that such antibodies play a role in neuronal degeneration by examining the behavioral and cellular effects of immunizing rats with the heavy neurofilament protein of Torpedo cholinergic neurons. The immunized rats developed antibodies which were specific to the heavy neurofilament protein of Torpedo cholinergic neurons and which cross-reacted with rat brain neurofilaments. Immunohistochemical studies revealed the accumulation of antibodies in the perikarya and neurites of neurons in the septum and hippocampus of the cholinergic neurofilament immunized rats and in white matter tracts in their forebrains. No such staining was seen in adjuvant immunized control rats. Behavioral tests revealed that rats immunized with the heavy cholinergic neurofilament protein performed significantly worse than controls in a T-maze alternation test and that their performance deteriorated profoundly after the introduction of a 20-s delay in the paradigm, indicating a deficit in short term memory. In contrast, both groups performed similarly in a T-maze discrimination test, indicating that long term reference memory was not affected by immunization with the heavy cholinergic neurofilament protein. Further experiments revealed that the rats immunized with the heavy cholinergic neurofilament protein were also deficient in a reversal of choice paradigm in a position discrimination test. These behavioral changes are similar to those previously observed following septohippocampal lesions and mimic some of the behavioral deficits associated with Alzheimer's disease. The association of antibodies to the heavy neurofilament protein of Torpedo cholinergic neurons with cognitive deficits in this animal model may replicate pathogenic processes in Alzheimer's disease and supports a role for such antibodies in the degeneration of cholinergic neurons in the disease.