Intrahippocampal Amyloid-β (1-40) Injections Injure Medial Septal Neurons in Rats

Abstract

Alzheimer's disease (AD) is a devastating disorder that leads to memory loss and dementia. Neurodegeneration of cholinergic neurons in the septum and other basal forebrain areas is evident in early stages of AD. Glutamatergic neurons are also affected early in AD. In these stages, amyloid-beta-peptide (A beta) plaques are present in the hippocampus and other cortices but not in the basal forebrain, which includes the septum. We postulate that early deposition of hippocampal A beta damages the axon terminals of cholinergic and glutamatergic septo-hippocampal neurons, leading to their degeneration. To determine the mechanisms underlying septal degeneration, fibrillar A beta 1-40 was injected into the Cornu Ammonis (CA1) hippocampal region of rats. Controls were injected with reverse peptide A beta 40-1. A 16\% reduction in NeuN+ cells was observed around the injection sites when compared to controls (p<0.05) one week after injections. Stereology was used to estimate the number of choline acetyl transferase (ChAT), glutamate and glutamic acid decarboxylase 67 (GAD67) immunoreactive septal neurons. Medial septal ChAT and glutamate immunoreactive neurons were reduced 38\% and 26\%, respectively by hippocampal injections of A beta 1-40 peptide in relation to controls. In contrast, the number of GAD67 inmunoreactive neurons was not significantly reduced. Apoptotic cells were detected in the medial septal region of A beta 1-40 treated animals but not in controls. These results indicate that limited A beta-induced hippocampal lesions lead to an overall damage of vulnerable septal neuronal populations, most likely by A beta interaction with septo-hippocampal axon terminals. Thus, axon terminals constitute an important target for novel therapeutics dedicated to control A beta-induced toxicity.