Impairment of adolescent hippocampal plasticity in a mouse model for Alzheimer's disease precedes disease phenotype

• Published in: PloS one Vol. 3; no. 7; p. e2759
• Main Authors: Hartl, Daniela, Rohe, Michael, Mao, Lei, Staufenbiel, Matthias, Zabel, Claus, Klose, Joachim
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.07.2008; Public Library of Science (PLoS)
• Subjects: Adolescence; Adolescents; Advertising executives; Age; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-protein; Amyloid precursor protein; Analysis; Animals; Apolipoproteins; Brain; Cell adhesion & migration; Cell cycle; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Child development; Cognitive ability; Developmental stages; Disease Models, Animal; Disease Progression; Electrophoresis, Gel, Two-Dimensional; Embryos; GAP-43 Protein - metabolism; Gel electrophoresis; Gene Expression Regulation; Genetic aspects; Genetic engineering; Genotype & phenotype; Hippocampal plasticity; Hippocampus; Hippocampus - embryology; Hippocampus - metabolism; Humans; Identification; Mass spectrometry; Mass spectroscopy; Medical research; Medicine; Mice; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurological Disorders; Neurological Disorders/Alzheimer Disease; Neuronal Plasticity; Neurons; Neuroscience; Phenotype; Plastic properties; Plasticity; Proteins; Proteomes; Proteomics; Proteomics - methods; Rodents; Senile plaques; Spots; Studies; Teenagers; Time Factors; Transgenic animals; Transgenic mice; Two dimensional models
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0002759

The amyloid precursor protein (APP) was assumed to be an important neuron-morphoregulatory protein and plays a central role in Alzheimer's disease (AD) pathology. In the study presented here, we analyzed the APP-transgenic mouse model APP23 using 2-dimensional gel electrophoresis technology in combination with DIGE and mass spectrometry. We investigated cortex and hippocampus of transgenic and wildtype mice at 1, 2, 7 and 15 months of age. Furthermore, cortices of 16 days old embryos were analyzed. When comparing the protein patterns of APP23 with wildtype mice, we detected a relatively large number of altered protein spots at all age stages and brain regions examined which largely preceded the occurrence of amyloid plaques. Interestingly, in hippocampus of adolescent, two-month old mice, a considerable peak in the number of protein changes was observed. Moreover, when protein patterns were compared longitudinally between age stages, we found that a large number of proteins were altered in wildtype mice. Those alterations were largely absent in hippocampus of APP23 mice at two months of age although not in other stages compared. Apparently, the large difference in the hippocampal protein patterns between two-month old APP23 and wildtype mice was caused by the absence of distinct developmental changes in the hippocampal proteome of APP23 mice. In summary, the absence of developmental proteome alterations as well as a down-regulation of proteins related to plasticity suggest the disturption of a normally occurring peak of hippocampal plasticity during adolescence in APP23 mice. Our findings are in line with the observation that AD is preceded by a clinically silent period of several years to decades. We also demonstrate that it is of utmost importance to analyze different brain regions and different age stages to obtain information about disease-causing mechanisms.