Brain Advance Access originally published online on July 14, 2006
Brain 2006 129(11):2992-3005; doi:10.1093/brain/awl176
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Selective vulnerability of different types of commissural neurons for amyloid ß-protein-induced neurodegeneration in APP23 mice correlates with dendritic tree morphology
1 Department of Neuropathology, University of Bonn Bonn 2 Department of Biochemistry, Adolf-Butenandt Institute Ludwig Maximilians University, Munich 3 Department of Neuropathology, Georg-August University Göttingen, Germany 4 Novartis Institutes for Biomedical Research Basel Basel, Switzerland 5 Gunma University School of Health Sciences, Maebashi Gunma, Japan
Correspondence to: Dietmar R. Thal, MD, Department of Neuropathology, University of Bonn, Sigmund Freud Strasse 25, D-53105 Bonn, Germany E-mail: Dietmar.Thal{at}uni-bonn.de
The amyloid ß-protein (Aß) is the main component of Alzheimer's disease-related senile plaques. Although Aß is associated with the development of Alzheimer's disease, it has not been shown which forms of Aß induce neurodegeneration in vivo and which types of neurons are vulnerable. To address these questions, we implanted DiI crystals into the left frontocentral cortex of APP23 transgenic mice overexpressing mutant human APP (amyloid precursor protein gene) and of littermate controls. 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 labelled commissural neurons were seen in APP23 mice compared with wild-type mice. A selective reduction of the heavily ramified type of neurons was observed in APP23 mice compared with wild-type animals at 5, 11 and 15 months of age, starting when the first Aß-deposits occurred in the frontocentral cortex at 5 months. The other two types of commissural neurons did not show alterations at 5 and 11 months. At 15 months, 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 time Aß-deposits were seen in the neo- and allocortex as well as in the basal ganglia and the thalamus. In summary, our results show that Aß 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 Aß-deposits in the neocortex, that is, with the detection of aggregated Aß. The involvement of additional neuronal subpopulations is associated with the expansion of Aß-deposition into further brain regions. The vulnerability of different types of neurons to Aß, thereby, is presumably related to the complexity of their dendritic morphology.
Key Words: Alzheimer's disease pathology; animal models; beta-amyloid; neurodegenerative mechanisms; selective vulnerability
Abbreviations: Aß, amyloid ß protein; APP, amyloid precursor protein; BDA, biotinylated dextran amine; ELISA, enzyme-linked immunosorbent assay; NFTs, neurofibrillary tangles; PFA, paraformaldehyde
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Received February 28, 2006. Revised April 20, 2006. Accepted June 7, 2006.
*Present address: DKFZ-German Cancer Research Center, D-69120 Heidelberg, Germany
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