ANIMAL-MODEL AND IN-VITRO STUDIES OF ANTI NEUROFILAMENT ANTIBODIES MEDIATED NEURODEGENERATION IN ALZHEIMERS-DISEASE

Alzheimer's disease (AD) is associated with serum antibodies directed specifically against phosphorylated epitopes highly enriched in the he avy neurofilament protein NF-H of cholinergic neurons. Prolonged immun ization of rats with these molecules but not with other NF-H isoforms results in cognitive impairments. This animal model, termed experiment al autoimmune dementia (EAD), supports a role for such antibodies in n eurodegeneration in AD. In the present study we investigated the cellu lar and immunological mechanisms underlying the cognitive defects in E AD. Immunohistochemical studies revealed that IgG accumulate in the se ptum, hippocampus and in the entorhinal cortex of the EAD rats. This i s accompanied by a marked reduction in the density of septal cholinerg ic neurons. An inverse correlation was observed between the level of I gG in the septum of individual EAD rats and the density of their septa l cholinergic neurons. Time course studies revealed that the decrease in the density of cholinergic neurons in the septum of EAD rats and th e accumulation of IgG in this brain area have the same time course and are both significant by three to four months following the initiation of immunization with cholinergic NF-H. The cognitive deficits of the EAD rats evolve more slowly and are pronounced only after six months f ollowing the initation of immunization. In vitro studies revealed that anti NF-H IgG bind to the outer surface of neurons in tissue cultures of rat forebrain and can affect neuronal viability. These AD and in v itro findings provide model systems for studying the mechanisms underl ying the neuropathological effects of specific anti NF-H antibodies.