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

Rentsch, P; Ganesan, K; Langdon, A; Konen, LM; Vissel, B

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

Rentsch, P Ganesan, K Langdon, A Konen, LM Vissel, B

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Publisher:: Frontiers
Publication Type:: Journal Article
Citation:: Frontiers in Aging Neuroscience, 2024, 16, pp. 1421900
Issue Date:: 2024

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Field	Value	Language
dc.contributor.author	Rentsch, P
dc.contributor.author	Ganesan, K
dc.contributor.author	Langdon, A
dc.contributor.author	Konen, LM
dc.contributor.author	Vissel, B
dc.date.accessioned	2025-01-28T05:50:56Z
dc.date.available	2024-06-03
dc.date.available	2025-01-28T05:50:56Z
dc.date.issued	2024
dc.identifier.citation	Frontiers in Aging Neuroscience, 2024, 16, pp. 1421900
dc.identifier.issn	1663-4365
dc.identifier.issn	1663-4365
dc.identifier.uri	http://hdl.handle.net/10453/184392
dc.description.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 A knock-in mice (hA -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, hA -KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hA -KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of A plaques in hA -KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hA -KI mice compared to WT, and LPS exposure in hA -KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology. Conclusion The study highlights the potential of hA -KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of A 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.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	Frontiers
dc.relation.ispartof	Frontiers in Aging Neuroscience
dc.relation.isbasedon	10.3389/fnagi.2024.1421900
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1109 Neurosciences, 1702 Cognitive Sciences
dc.subject.classification	3209 Neurosciences
dc.subject.classification	5202 Biological psychology
dc.title	Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models
dc.type	Journal Article
utslib.citation.volume	16
utslib.location.activity	Switzerland
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1109 Neurosciences
utslib.for	1702 Cognitive Sciences
utslib.copyright.status	open_access	*
pubs.consider-herdc	true
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-01-28T05:50:54Z
pubs.publication-status	Published
pubs.volume	16

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 A knock-in mice (hA -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, hA -KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hA -KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of A plaques in hA -KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hA -KI mice compared to WT, and LPS exposure in hA -KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology. Conclusion The study highlights the potential of hA -KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of A 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.

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http://hdl.handle.net/10453/184392