Modeling Alzheimer’s disease in mice by selectively lesioning the cholinergic basal forebrain

Abstract

One pathological feature of Alzheimer’s disease (AD) is the degeneration of the cholinergic basal forebrain (CBF). The importance of this degeneration in AD is suggested by the observation that the degree of CBF degeneration correlates with the degree of dementia. To model CBF degeneration in mice, we injected the immunotoxin mu-p75-saporin or saline vehicle into the left lateral ventricle. This immunotoxin is designed to selectively kill the neurons of the mouse CBF by targeting the p75 nerve growth factor receptor expressed by CBF neurons. After recovery from immunotoxin injection, the mice were tested using a battery of learning memory tests. Immunotoxin injection did not cause any change in spontaneous motor activity or cued fear conditioning, but it did produce a deficit in contextual fear conditioning and passive avoidance learning. Immunotoxin-injected mice also showed a minor impairment in motor coordination as revealed by testing on the accelerating rotarod. Histochemistry for acetylcholinenesterase showed that immunotoxin injection resulted in a substantial loss of cholinergic fibers in target fields of the CBF such as the hippocampus and neocortex. Immunohistochemistry for calbindin-D28K showed that there was no loss of cerebellar Purkinje cells, which, like the CBF, express p75. Future work will further determine the selectivity of mu-p75-saporin by performing immunohistochemistry for p75 and parvalbumin in the CBF of immunotoxin-injected mice. In summary, the present data support the use of mu-p75-saporin to model key pathological and behavioral features of AD in the laboratory mouse. The utility of this model will be to serve as a screening tool for new drug therapies, especially when used in combination with transgenic mouse models of other pathological features of AD.