Researchers led by Takaomi Saido and Hiroki Sasaguri at the RIKEN Center for Brain Science, Wako, Japan, have developed a new, double knock-in model of amyloidosis. The mice produce human Aβ43 and Aβ42 in the brain, and they begin to deposit dense-core amyloid plaques in the cortex and hippocampus before they are 3 months old. They also develop rampant neuroinflammation. Saido believes the mice will change the landscape of experimental AD research. The paper was uploaded to bioRXiv on April 30.
“This new mouse model is a very welcome addition to the toolbox of AD mouse models. It avoids the Arctic mutation, which is helpful for some questions, but not necessarily for others,” wrote Stefan Lichtenthaler, German Center for Neurodegenerative Disease, Munich, to Alzforum (see comment below).
Saido and colleagues had previously developed APP knock-in mice as an alternative to a plethora of models that overexpress the human amyloid precursor protein and/or human presenilin. They argued that knock-ins more faithfully recapitulate the pathology that occurs in the human brain, since they are devoid of potential overexpression and genomic rearrangement artifacts (Apr 2014 webinar).
Their APP-NL-F knock-ins express APP with the Swedish and Iberian mutations that cause autosomal-dominant AD. Because these need more than a year to develop an appreciable plaque load, the researchers also made a version containing the Arctic mutation. This glutamic-acid-to-glycine swap at position 22 of the Aβ sequence makes the peptide much more likely to aggregate. As such, these APP-NL-G-F mice begin to lay down plaques in the brain before they are 2 months old.
Alas, this Arctic mutation has its downsides. Proteases in the brain have a harder time digesting Aβ peptides with the mutation, and it may bind less avidly to Aβ antibodies being tested as immunotherapies. In short, changing the peptide also limits its relevance.
Enter the new double knock-ins. Co-first authors Kaori Sato, Naoto Wakamura, and colleagues crossed the APP-NL-F mice with a knock-in expressing presenilin 1 with the P117L mutation that causes familial AD. The APP-NL-F/PS1 P117L double knock-ins produce about 25-fold more Aβ than does the NL-F single knock-in, and they have prominent amyloidosis by 12 months. Plaques are often of the dense-core variety, which is associated with AD. The double knock-ins have about threefold and sixfold more dense-core plaques in the hippocampus and cortex, respectively, than do the APP-NL-F mice. Microglial inflammation is rampant in the cortex and hippocampus, as well.
Curiously, microglia are much more active in the hippocampi of the double knock-ins than in the hippocampi of the Arctic APP-NL-G-F single knock-ins, despite similar plaque loads. The authors believe higher levels of Aβ43 and dense-core plaques in the double knock-ins might explain the difference. Microglia might even be responsible for laying down dense-core plaques as a way to protect the brain (Apr 2021 news).—Tom Fagan
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- Sato K, Watamura N, Fujioka R, Mihira N, Sekiguchi M, Nagata K, Ohshima T, Saito T, Saido TC, Sasaguri H. New App knock-in mice that accumulate wild-type human Aβ as rapidly as AppNL-G-F mice exhibit intensive cored plaque pathology and neuroinflammation. bioRxiv. April 30, 2021.