Pyk2 overexpression in postsynaptic neurons blocks amyloid β_1-42-induced synaptotoxicity in microfluidic co-cultures

Area of Science:

• Neuroscience
• Genetics
• Biotechnology

Background:

• Genome-wide association studies (GWAS) have identified Alzheimer's disease (AD) genetic risk factors, but their mechanisms remain unclear.
• Synapse loss is an early pathological hallmark of AD, making the study of AD risk genes' impact on synaptic function critical.

Purpose of the Study:

• To develop a microfluidic co-culture system for studying Alzheimer's disease (AD)-related synaptotoxicity.
• To investigate the impact of amyloid-beta (Aβ) peptides on synaptic connectivity and the protective role of AD genetic risk factors.

Main Methods:

• A microfluidic device physically isolated synapses for chronic exposure to amyloid-beta (Aβ) peptides.
• Primary hippocampal neurons were co-cultured with cells overexpressing wild-type or mutated amyloid precursor protein (APP).
• Synaptic connectivity was assessed, and the effects of Aβ targeting antibodies and protein tyrosine kinase 2 beta (PTK2B) were evaluated.

Main Results:

• Exposure to amyloid-beta (Aβ)_1-42 at nanomolar concentrations significantly decreased synaptic connectivity in hippocampal neurons.
• Low molecular weight amyloid-beta (Aβ) oligomers were identified as the likely toxic species responsible for synaptotoxicity.
• Overexpression of protein tyrosine kinase 2 beta (PTK2B) in postsynaptic neurons conferred protection against amyloid-beta (Aβ)_1-42-induced synaptotoxicity.

Conclusions:

• The developed lab-on-a-chip device offers a physiologically relevant model for studying Alzheimer's disease (AD) synaptotoxicity.
• This model is suitable for assessing the specific roles of pre- and postsynaptic genetic risk factors in AD pathogenesis.
• Targeting amyloid-beta (Aβ) oligomers and leveraging protective genetic factors like PTK2B may offer therapeutic strategies for Alzheimer's disease (AD).