Lesions and dysfunctions of the nucleus basalis as Alzheimer's disease models: general and critical overview and analysis of the long-term changes in several excitotoxic models.

Abstract

The cholinergic hypothesis of Alzheimer's Disease (AD) has led to a number of animal models to study in vivo the pathogeny of cortical cholinergic involution. The lesion of the cholinergic neurons of the basal forebrain, especially of the nucleus basalis magnocellularis (nbm) of rodents, has been the most utilized method for obtaining these models. Toxic substances such as quinolic, kainic, NMDA, ibotenic and quisqualic acids, the specific cholinergic toxin AF64, amyloid, and antibodies to neurotrophic factors; etc, have been used to produce such lesions. These investigations have helped our understanding of the role of cerebral cholinergic innervation in cognitive disorders and their treatments. However, this research has provided conflicting results, and much controversy has developed surrounding the role of the cholinergic systems and the suitability of these models. It is very important to take into account the exact type of nbm/cortical lesion produced, and its evolution, if meaningful results are to be obtained. This review covers the theoretical and practical use of nbm lesion models, and examines the main positive and negative results obtained by different authors in the light of our own observations on the long-term (3 years) morphological and biochemical changes that occur in several kinds of nbm-lesion model rats. The changes seen were very different, but many of them were increased up to the end of life with no clear relationship with the development of the original lesion.