Immunization of rats with cholinergic neurons induces behavioral deficits

We have previously shown that sera from patients with Alzheimer's disease (AD) contain a significantly high level of antibodies to the cell bodies (Perikarya; PK) but not to the nerve terminals (synaptosomes) of purely cholinergic neurons from the electric fish Torpedo. In the present study we examined the effect of repeated immunization of rats with either of these antigens for one year. Immunoblot studies revealed that sera of cholinergic PK immunized rats contained a high level of antibodies to cholinergic PK proteins, in particular to a 200 kilodalton protein, to which there are specifically high levels of antibodies in AD. Sera from rats immunized with cholinergic synaptosomes and from control rats contained very low levels of these antibodies. Behavioral studies performed one year after the initial immunization revealed that the cholinergic PK immunized rats were impaired in spatial learning and memory tasks (Morris swim test and T-maze alternation) when compared to control rats and that the synaptosome-immunized rats showed no such deficit. In contrast, the three groups performed similarly in general activity, active avoidance and conditioned emotional response tests. Further experiments revealed that the cholinergic PK immunized rats displayed a significant deficit in short term memory. The association of antibodies to cholinergic neurons with cognitive deficits in this rat model suggests that such antibodies may be involved in the pathogenesis of AD.