| First Author | Kulic L | Year | 2012 |
| Journal | Transl Psychiatry | Volume | 2 |
| Pages | e183 | PubMed ID | 23149447 |
| Mgi Jnum | J:282772 | Mgi Id | MGI:6378944 |
| Doi | 10.1038/tp.2012.109 | Citation | Kulic L, et al. (2012) Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Abeta APP mutation. Transl Psychiatry 2:e183 |
| abstractText | Pathogenic amyloid-beta peptide precursor (APP) mutations clustered around position 693 of APP-position 22 of the Abeta sequence--are commonly associated with congophilic amyloid angiopathy (CAA) and intracerebral hemorrhages. In contrast, the Osaka (E693Delta) intra-Abeta APP mutation shows a recessive pattern of inheritance that leads to AD-like dementia despite low brain amyloid on in vivo positron emission tomography imaging. Here, we investigated the effects of the Osaka APP mutation on Abeta accumulation and deposition in vivo using a newly generated APP transgenic mouse model (E22DeltaAbeta) expressing the Osaka mutation together with the Swedish (K670N/M671L) double mutation. E22DeltaAbeta mice exhibited reduced alpha-processing of APP and early accumulation of intraneuronal fibrillar Abeta oligomers associated with cognitive deficits. In line with our in vitro findings that recombinant E22Delta-mutated Abeta peptides form amyloid fibrils, aged E22DeltaAbeta mice showed extracellular CAA deposits in leptomeningeal cerebellar and cortical vessels. In vitro results from thioflavin T aggregation assays with recombinant Abeta peptides revealed a yet unknown antiamyloidogenic property of the E693Delta mutation in the heterozygous state and an inhibitory effect of E22Delta Abeta42 on E22Delta Abeta40 fibrillogenesis. Moreover, E22Delta Abeta42 showed a unique aggregation kinetics lacking exponential fibril growth and poor seeding effects on wild-type Abeta aggregation. These results provide a possible explanation for the recessive trait of inheritance of the Osaka APP mutation and the apparent lack of amyloid deposition in E693Delta mutation carriers. |
