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Coutts, Juliane

University of British Columbia

We aimed to investigate the role of cSNK-bearing oligomers in hippocampal neurogenesis disturbances associated with AD and assess the potential of mAb5E3 in mitigating these effects. Aged male and female APPswe/PSEN1ΔE9 AD model mice were treated with mAb5E3 for 6 weeks. The effect of passive immunization on adult hippocampal neurogenesis was determined by quantifying the rate of survival in 4-week-old newborn granule cells by immunohistochemical detection of the DNA marker BrdU. Additionally, we analyzed immediate early gene (IEG) expression to assess changes in dentate network activity in response to spatial learning. Behavioral outcomes were assessed via open field exploration, novel object, and location recognition tasks. We found that mAb5E3 significantly increased the survival of newborn hippocampal neurons. Consistent with the role of newborn neurons in modulating the level of activity in the DG, we found that survival rates were inversely related to IEG expression, such that an increase in neurogenesis was associated with a commensurate decrease in the activity levels within the overall GC population. In the novel object recognition task, we found that mAb5E3-treated mice spent significantly more time exploring the novel object compared to the familiar one. This observed bias exceeding the level expected by chance alone suggests an ability to discriminate previously encountered objects. This study extends the understanding of the role of cSNK-bearing AβOs in AD pathogenesis, providing evidence of their role in AD-related neurogenesis abnormalities. Moreover, our findings further validate the therapeutic potential of mAb5E3, providing additional insight into its mechanism and efficacy.

Text

2023-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85763

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/