Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models

Peggy Rentsch; Kiruthika Ganesan; Alexander Langdon; Lyndsey M Konen; Bryce Vissel

doi:10.3389/fnagi.2024.1421900

Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models

Front Aging Neurosci. 2024 Jul 8:16:1421900. doi: 10.3389/fnagi.2024.1421900. eCollection 2024.

Authors

Peggy Rentsch^#^{1

2}, Kiruthika Ganesan^#³, Alexander Langdon³, Lyndsey M Konen¹, Bryce Vissel^{1

2}

Affiliations

¹ Centre for Neuroscience and Regenerative Medicine, St. Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
² UNSW St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
³ School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.

^# Contributed equally.

Abstract

Background: Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance.

Methods: In the current study, we exposed humanized Aβ knock-in mice (hAβ-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice.

Results: At the early time point of 24 weeks, hAβ-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAβ-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aβ plaques in hAβ-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAβ-KI mice compared to WT, and LPS exposure in hAβ-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology.

Conclusion: The study highlights the potential of hAβ-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aβ plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.

Keywords: J20; dendritic spine density; humanized Aβ; lipopolysaccharide; neuroinflammation; sporadic and familial Alzheimer's disease.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors declare that this study received funding from Helen and David Baffsky, Douglas and Alison Battersby/Veruse Pty Ltd., Boyarsky Family, Charlie Brockhoff, Andrew Michael and Michele Brooks, Tim Capelin, Pia Clinton- Tarestad, Dr Sophie and Mr Richard Gelski/Lawsam Foundation, John Gibb, Justin Greiner, Gordon Grieve, Gerry Harvey, Richard Holden/Station Capital, Tony and Vivienne Howland Rose, ISG Foundation, David and Lynn King, The Kirsch Foundation, Sam and Barbara Linz, Neill and Kathy Miller, Richard, Adrian, and Tom O'Connor, Katie Page, Marnie and Gary Perlstein, S & C Roth Family Foundation, John and Debbie Schaffer, David and Melanie Schwartz, Sealy of Australia and the Dyer Family, Julian Segal, John Singleton, Ashley Stephenson, Alex Sundich/Bridge Street Capital, and Tasmea Limited. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.