Integration of Microfluidic Devices with Microelectrode Arrays to Functionally Assay Amyloid-ß-Induced Synaptotoxicity.
ACS Biomater Sci Eng
; 10(3): 1856-1868, 2024 03 11.
Article
en En
| MEDLINE
| ID: mdl-38385618
ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease and the most frequent cause of dementia. It is characterized by the accumulation in the brain of two pathological protein aggregates amyloid-ß peptides (Aß) and abnormally phosphorylated tau. The progressive cognitive decline observed in patients strongly correlates with the synaptic loss. Many lines of evidence suggest that soluble forms of Aß accumulate into the brain where they cause synapse degeneration. Stopping their spreading and/or targeting the pathophysiological mechanisms leading to synaptic loss would logically be beneficial for the patients. However, we are still far from understanding these processes. Our objective was therefore to develop a versatile model to assay and study Aß-induced synaptotoxicity. We integrated a microfluidic device that physically isolates synapses from presynaptic and postsynaptic neurons with a microelectrode array. We seeded mouse primary cortical cells in the presynaptic and postsynaptic chambers. After functional synapses have formed in the synaptic chamber, we exposed them to concentrated conditioned media from cell lines overexpressing the wild-type or mutated amyloid precursor protein and thus secreting different levels of Aß. We recorded the neuronal activity before and after exposition to Aß and quantified Aß's effects on the connectivity between presynaptic and postsynaptic neurons. We observed that the application of Aß on the synapses for 48 h strongly decreased the interchamber connectivity without significantly affecting the neuronal activity in the presynaptic or postsynaptic chambers. Thus, through this model, we are able to functionally assay the impact of Aß peptides (or other molecules) on synaptic connectivity and to use the latter as a proxy to study Aß-induced synaptotoxicity. Moreover, since the presynaptic, postsynaptic, and synaptic chambers can be individually targeted, our assay provides a powerful tool to evaluate the involvement of candidate genes in synaptic vulnerability and/or test therapeutic strategies for AD.
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Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Neurodegenerativas
/
Enfermedad de Alzheimer
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Biomater Sci Eng
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos