2016 Fiscal Year Annual Research Report
| Project/Area Number |
15K18369
|
|---|
| Research Institution | Institute of Physical and Chemical Research |
|---|
Principal Investigator |
NILSSON PER 国立研究開発法人理化学研究所, 脳科学総合研究センター, 研究員 (10568934)
|
|---|
| Project Period (FY) |
2015-04-01 – 2017-03-31
|
| Keywords | Autophagy / Aβ metabolism / Neurodegeneration / Alzheimer’s disease / APP knock-in mouse model |
|---|
| Outline of Annual Research Achievements |
We generated autophagy deficient APP knock-in mice by breeding mice with a conditional knock out of autophagy-related gene 7 (Atg7) and a CamKII-Cre-recombinase transgenic mice with APP-knock-in (APPNL-F) mice. We could confirm a significant decreased Aβ plaque load in these mice, consistent with previous data obtained with autophagy-deficient APP transgenic mice (Atg7 cKO x APP Tg) indicating that autophagy plays an important role in Aβ metabolism also under physiological APP levels. In addition, genetic deletion of Atg7 leads to a significant accumulation of intracellular Aβ in the pyramidal neurons in CA1 region, also consistent with previous data obtained from Atg7 x APP Tg mice. This together shows an important role for autophagy in Aβ metabolism. Immunoelectron experiments were attempted to determine the subcellular localization of intracellular Aβ, but have to be repeated due to low signal. A screen to knockdown proteins known to be involved in autophagy-mediated secretory routes has been performed which indicate the involvement of multivesicular bodies in the secretion of Aβ. However, no neurodegeneration was found by histological or MRI experiments which was observed previously in the Atg7 cKO x APP Tg mice. This may indicate that the neurodegeneration is an artefact from APP overexpression. Proteomic analysis of cortical and hippocampal brain samples will be performed with collected aged brain samples.
|
