APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Apolipoprotein E4 (APOE4) is a major genetic risk factor for Alzheimer's disease.
• APOE4's impact on early brain development and neurodevelopmental processes is not fully understood.
• Existing research primarily focuses on APOE4's role in aging, not early-life neurodevelopment.

Purpose of the Study:

• To investigate the influence of APOE4 on the development of cortical excitatory and inhibitory neurons.
• To examine how APOE4 affects neurodevelopmental processes and functional neural network establishment.
• To understand the early-life impact of APOE4 on brain structure and connectivity.

Main Methods:

• Utilized human induced pluripotent stem cell-derived cortical and ganglionic eminence organoids (COs and GEOs).
• Analyzed changes in neuronal and glial cell populations and their differentiation pathways.
• Employed multi-electrode array recordings in assembloids to assess neural network function.

Main Results:

• APOE4 reduced cortical neuron numbers while increasing glial cells by promoting gliogenic transcriptional programs.
• APOE4 enhanced the proliferation and differentiation of GABAergic progenitors, leading to increased GABAergic neurons.
• Neural network recordings demonstrated that APOE4 disrupts function, causing heightened excitability and synchronicity.

Conclusions:

• APOE4 significantly influences cortical neurodevelopment, impacting both neuronal and glial cell populations.
• The study reveals early and persistent alterations in neural network function due to APOE4.
• Findings provide novel insights into how APOE4 affects early brain development and the establishment of functional neural networks.