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[210604 Àú³Î¹ßÇ¥] New App knock-in mice that accumulate wild-type human A¥â as rapidly as App NL-G-F mice exhibit intensive cored plaque pathology and neuroinflammation.

Á¤¼±¿ì ¦¢ 2021-06-03

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doi: https://doi.org/10.1101/2021.04.30.442122


bioRixv

New App knock-in mice that accumulate wild-type human A¥â as rapidly as

App NL-G-F mice exhibit intensive cored plaque pathology and neuroinflammation.

Kaori Sato1,2,+, Naoto Watamura1,+, Ryo Fujioka1, Naomi Mihira1, Misaki Sekiguchi1, Kenichi

Nagata3, Toshio Ohshima2, Takashi Saito4, Takaomi C. Saido1* and Hiroki Sasaguri1* 


Abstract

We previously developed single App knock-in mouse models of Alzheimer¡¯s disease (AD), harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). These models showed amyloid ¥â peptide (A¥â) pathology, neuroinflammation and cognitive impairment in an age-dependent manner. The former line exhibits extensive pathology as early as 6 months but is unsuitable for investigating A¥â metabolism and clearance because the Arctic mutation renders A¥â resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-A¥â antibodies. The weakness of the latter model is that it may take as long as 18 months for the pathology to become prominent. We have thus generated a new model that exhibits early deposition of wild-type human A¥â by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD.





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