%0 Journal Article %J J Alzheimers Dis %D 2016 %T Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease. %A Weissmann, Robert %A Hüttenrauch, Melanie %A Kacprowski, Tim %A Bouter, Yvonne %A Pradier, Laurent %A Bayer, Thomas A %A Kuss, Andreas W %A Wirths, Oliver %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Disease Models, Animal %K Gene Expression Profiling %K Male %K Mice %K Mice, Transgenic %K Nerve Degeneration %K Presenilin-1 %K Transcriptome %X

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.

%B J Alzheimers Dis %V 50 %P 397-409 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639971?dopt=Abstract %R 10.3233/JAD-150745 %0 Journal Article %J J Alzheimers Dis %D 2016 %T N-truncated Aβ2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models. %A Savastano, Adriana %A Klafki, Hans %A Haußmann, Ute %A Oberstein, Timo Jan %A Muller, Petr %A Wirths, Oliver %A Wiltfang, Jens %A Bayer, Thomas A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blotting, Western %K Brain %K Cerebral Amyloid Angiopathy %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Transgenic %K Plaque, Amyloid %X

According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.

%B J Alzheimers Dis %V 49 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26529393?dopt=Abstract %R 10.3233/JAD-150394