Amyloid β-peptide-induced progressive neurodegeneration in an APP-transgenic mouse model for Alzheimer’s disease

Abstract

The amyloid beta-protein (Abeta) is the main component of Alzheimer's disease (AD)-related senile plaques. In the human brain Abeta-deposition occurs in a hierarchical sequence in which different areas of the brain become involved. It is not clear whether this sequence shows the time course of Abeta-deposition or just different pathology in different individuals. Although Abeta is associated with the development of AD it has not been shown which forms of Abeta induce neurodegeneration in vivo, which types of neurons are vulnerable and whether Abeta-induced neurodegeneration increases with the progression of Abeta-pathology. To address these questions, DiI-crystals were implanted into the left frontocentral cortex of APP23 transgenic mice overexpressing mutant human APP and of wild-type littermates. In parallel, immunohistochemistry for Abeta-plaque detection was performed in 3-, 5-, 11-, 15- and 25-month-old APP23 mice and wild-type littermates. Traced commissural neurons in layer III of the right frontocentral cortex were quantified in 3-, 5-, 11-, and 15-month-old mice. Three different types of commissural neurons were traced. At 3 months of age no differences in the number of labeled commissural neurons were seen in APP23 mice compared to wild-type mice. A selective reduction of the heavily ramified type of neurons was observed in APP23 mice compared to wild-type animals at 5, 11, and 15 months of age, starting with the deposition of Abeta-plaques occurred in the frontocentral cortex at 5 months of age. The other two types of commissural neurons did not show alterations in 5- and 11-month animals. At 15 months of age, the number of traced sparsely ramified pyramidal neurons was reduced in addition to that of the heavily ramified neurons in APP23 mice compared with wild-type mice. At this point in time Abeta-deposits were seen in the neo- and allocortex as well as in the basal ganglia and the thalamus. At 25 months of age Abeta-deposits were also seen at the brainstem. In summary, the results show that 1) Abeta-deposition in APP23 mice follows a similar sequence as in human brain, in which the different areas become step-by-step involved in beta-amyloidosis, 2) this step-by-step regional involvement represents the time course of Abeta-deposition in the brain, and 3) Abeta thereby, induces progressive degeneration of distinct types of commissural neurons. Degeneration of the most vulnerable neurons starts in parallel with the occurrence of the first fibrillar Abeta deposits in the neocortex. The selective vulnerability of different types of neurons to Abeta is presumably related to the complexity of their dendritic morphology. In so doing, these results support Abeta to be the major therapeutic target for AD treatment in pre-clinical as well as in late stages of the disease.