The Therapeutic Effects Of Aβ Oligomer-selective Monoclonal Antibody Treatment On Bigenic Mouse Model Of Alzheimer's Disease

Alzheimer's disease (AD) is a kind of age related neurodegenerative disease with the main clinical manifestations of cognitive impairment. Recently, Aβ oligomers are recognized as the main causative agent of AD in early neuron injury and pathogenesis. Based on our previous work, here we are going to investigate the effects of treatment of Aβ oligomer-selective monoclonal antibody (MAb) A8to AD bigenic mouse model in early stage.The4-month-old APPswe/PS1△E9bigenic mice were intraperitoneally injected with A8monoclonal antibody. In order to detect improvement in learning and memory behaviors, Morris Water Maze (MWM) was performed8weeks later. Mice cerebral homogenate were prepared with RIPA lysis buffer. Aβ1-42oligomers, total Aβ, Aβ1-42, Aβ1-40and phosphorylated tau (p-tau) were detected through Western blot; hippocampal ultrastructural pathology in thin section was observed through transmission electron microscopy (TEM). Based on the sequence of light and heavy chain variable region of A8, expression vector of human-mouse chimeric antibody were constructed, stable cell lines were established and identified after dhFr-auxotrophic media screening.The MWM results showed that in the fourth day of the place navigation test, escape latency (the incubation period) in A8group was significantly decreased (p<0.05); in spatial probe test the A8mice escape latency was significantly shorter (p<0.05). Supernatants and sediments of the mice brain homogenate were detected by Western blot, Aβ oligomers(p<0.01), total Aβ(p<0.01), Aβ1-42(p<0.05) and phosphorylated (Thr231) tau protein levels(p<0.01) were reduced in A8group compared with control groups(APP/PS1control and IgG treatment control). However there was no significant change in the level of Aβ1-40(p>0.05). TEM results showed that in mice brain hippocampus of A8group, the number of synapses were significantly increased than the control group mice. Chimeric antibody Ch-A8 specifically recognized Aβ1-42oligomer (A450=2.2265±0.3353), which was similar with the results of MAb A8(A450=2.525±0.2153).In summary, our study demonstrates that the A8MAb treatment has therapeutic effects on AD bigenic mouse model; A8functional human-mouse chimeric could be constructed and expressed through variable region in the genes of light and heavy chain of A8. Our study provides an effective tool for further humanization and the development of AD therapy.