Dispersible amyloid β-protein oligomers, protofibrils, and fibrils represent diffusible but not soluble aggregates: their role in neurodegeneration in amyloid precursor protein (APP) transgenic mice.

Soluble amyloid β-protein (Aβ) aggregates have been identified in the Alzheimer's disease (AD) brain. Dispersed Aβ aggregates in the brain parenchyma are different from soluble, membrane-associated and plaque-associated solid aggregates. They are in mixture with the extra- or intracellular fluid but can be separated from soluble proteins by ultracentrifugation. To clarify the role of dispersible Aβ aggregates for neurodegeneration we analyzed 2 different amyloid precursor protein (APP)-transgenic mouse models. APP23 mice overexpress human mutant APP with the Swedish mutation. APP51/16 mice express high levels of human wild type APP. Both mice develop Aβ-plaques. Dendritic degeneration, neuron loss, and loss of asymmetric synapses were seen in APP23 but not in APP51/16 mice. The soluble and dispersible fractions not separated from one another were received as supernatant after centrifugation of native forebrain homogenates at 14,000 × g. Subsequent ultracentrifugation separated the soluble, i.e., the supernatant, from the dispersible fraction, i.e., the resuspended pellet. The major biochemical difference between APP23 and APP51/16 mice was that APP23 mice exhibited higher levels of dispersible Aβ oligomers, protofibrils and fibrils precipitated with oligomer (A11) and protofibril/fibril (B10AP) specific antibodies than APP51/16 mice. These differences, rather than soluble Aβ and Aβ plaque pathology were associated with dendritic degeneration, neuron, and synapse loss in APP23 mice in comparison with APP51/16 mice. Immunoprecipitation of dispersible Aβ oligomers, protofibrils, and fibrils revealed that they were associated with APP C-terminal fragments (APP-CTFs). These results indicate that dispersible Aβ oligomers, protofibrils, and fibrils represent an important pool of Aβ aggregates in the brain that critically interact with membrane-associated APP C-terminal fragments. The concentration of dispersible Aβ aggregates, thereby, presumably determines its toxicity.

Rijal Upadhaya A ，Capetillo-Zarate E ，Kosterin I ，Abramowski D ，Kumar S ，Yamaguchi H ，Walter J ，Fändrich M ，Staufenbiel M ，Thal DR ... -  《-》

The type of Aβ-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid β-peptide (APP48) transgenic mice.

Rijal Upadhaya A ，Scheibe F ，Kosterin I ，Abramowski D ，Gerth J ，Kumar S ，Liebau S ，Yamaguchi H ，Walter J ，Staufenbiel M ，Thal DR ... -  《Acta Neuropathologica Communications》

[Involvement of beta-amyloid in the etiology of Alzheimer's disease].

Tomiyama T 《-》

Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein.

Gomes LA ，Hipp SA ，Rijal Upadhaya A ，Balakrishnan K ，Ospitalieri S ，Koper MJ ，Largo-Barrientos P ，Uytterhoeven V ，Reichwald J ，Rabe S ，Vandenberghe R ，von Arnim CAF ，Tousseyn T ，Feederle R ，Giudici C ，Willem M ，Staufenbiel M ，Thal DR ... -  《-》

Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease.

Rijal Upadhaya A ，Kosterin I ，Kumar S ，von Arnim CA ，Yamaguchi H ，Fändrich M ，Walter J ，Thal DR ... -  《-》