Animal Models of Age-Related Dementia: Neurobehavioral Dysfunctions in Autoimmune Mice MICHAEL J. FORSTER AND HARBANS LAL Department of Pharmacology, Texas College of Osteopathic Medicine 3.5’00 Camp Bowie Boulevard, Fort Worth, TX 76107 zyxwvutsrqponmlkjihgfedcbaZYXWVU FORSTER, M. J. AND H. LAL. Animal models of age-r&red dementia: Neurobrhavioral d@iinctions in autnimmune mice. BRAIN RES BULL 25(3) 503-516, 1990.-The development of strategies for treatment of Alzheimer‘s disease and other age-associated dementias is an important goal of research in the neurosciences. It is suggested that advances in understanding of the etiology of those disorders would provide the most obvious avenues to development of preventative treatments. Research findings from both clinical investigations and studies of animal models are presented which suggest a neuroimmunologic component in age-associated dementia. Clinical studies suggest an association between dementia and brain-reactive autoantibodies in subsets of patients with Alzheimer‘s disease. Studies of mice suggest that: 1) when compared with normal genotypes, mutant mice with accelerated autoimmunity show learning and memory impairments at earlier chronological ages; 2) the learning and memory deficits of autoimmune and normal mice are qualitatively similar; 3) the behavioral deficits of normal aged and autoimmune mice are sensitive to similar pharmacologic interventions. Overall, these findings suggest that intervention strategies targeting the immune system might be useful in the treatment or pre~,ention of aging-associated dementia. Autoimmune mice would be useful as models for the development and testing of such immune-based interventions. Alzheimer’s disease Learning Memory MRLiMpJ-lpr MRL/MpJ- -t NZBiBlNJ Habituation Brain-reactive antibodies BXSBiMpJ CS7BL/6NNia IDEALLY, an animal model of a human neuropathological condition should exhibit ali of the behavioral and neurologicai dysfunctions known to be associated with the clinical disorder. In addition, the model should incorporate pathologic processes sim- ilar to the target condition, and it should exhibit a similar response to therapeutic intervention. However, as a reading of the papers in this series will indicate, not all of these conditions need to be satisfied for an animal model to be useful. In fact, the degree to which the specific criteria of a model are satisfied usually depends upon the specific purpose for which the model was applied. With respect to research in Alzheimer’s disease, one important goal has been to develop intervention strategies for immediate reversal of symptoms. A reasonable approach to accomplishing that goal would be to test potential inte~entions in animal models with experimental lesions engineered to mimic the fund~ental neuro- logical determinants of Alzheimer’s dementia according to current understanding [cf. (47, 73, 10.5, 117)]. In this case, the resem- blance between the clinical condition and the model exists at the level of behavior and neuropathology but not necessarily at the level of etiology. For a successful treatment to be identified, only the neuropathological lesion needs to be “correct,” whereas the mechanism which produced the lesion does not necessarily need to be the same as the clinical condition. If the goal of a model system is to develop strategies to prevent or alleviate age-associated dementia, the “ correctness” of the etiological factors which produced the dementia-related neuropa- thology in the model are more impo~ant than the similarity of the neuropathological lesion to the true clinical condition. In this regard. animais exhibiting “spontaneous” age-related behavioral deficits and neuropathology are extremely valuable, because the deficits displayed may involve mechanisms similar to those involved in human aging and dementia. The pathological pro- cesses identified in these models should suggest interventions which, if successful in the model, could be applied to human dementia as well. In this review we will present research findings from our studies of genetically defined mice with spontaneous age-related behavioral deficits, and we will attempt to relate these findings to current understanding of the etiology of aging-associ- ated cognitive decline and Aizheimer’s disease. Our studies have focused specifically upon the potential role of autoimmunity and other immunopathological changes in aging-associated dementia, and we will therefore review some of the literature supporting the plausibility of such an etiology. NEUROIMMUNOLOGY OF AGING-ASSOCIATED DEMENTIA Alzheimer’s disease is an age-associated condition involving progressive and severe loss of recent memory capacity and other intellectual functions, a period of complete dependence, and a 503