Validation of a functional human AD model with four AD therapeutics utilizing patterned iPSC-derived cortical neurons integrated with microelectrode arrays.

Autor:	Caneus J; University of Central Florida., Autar K; University of Central Florida., Akanda N; University of Central Florida., Grillo M; University of Central Florida., Long C; Hesperos Inc., Jackson M; Hesperos Inc., Lindquist S; Hesperos Inc., Guo X; University of Central Florida., Morgan D; Michigan State University., Hickman JJ; University of Central Florida.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 May 20. Date of Electronic Publication: 2024 May 20.
DOI:	10.21203/rs.3.rs-4313679/v1
Abstrakt:	Preclinical methods are needed for screening potential Alzheimer's disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. A potential functional parameter to be monitored is long-term potentiation (LTP), which is a correlate of learning and memory, that would be one of the first functions effected by AD onset. Mature human iPSC-derived cortical neurons and primary astrocytes were co-cultured on microelectrode arrays (MEA) where surface chemistry was utilized to create circuit patterns connecting two adjacent electrodes to model LTP function. LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42 induced LTP impairment. The results presented here illustrate the significance of the system as a validated platform that can be utilized to model and study MCI AD pathology, and potentially for the pre-MCI phase before the occurrence of significant cell death. It also has the potential to become an ideal platform for high content therapeutic screening for other neurodegenerative diseases. Competing Interests: Conflict of Interest: The authors confirm that competing financial interests exist but there has been no financial support for this research that could have influenced its outcome. The only author with competing interest is J.H. who has ownership interest and is Chief Scientist and member of the Board of Directors in a company that may benefit financially as a result of the outcomes of the research or work reported in this publication.
Databáze:	MEDLINE
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