Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Cell Biology
• Genomics

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaques, but the role of microglia in neurodegeneration remains unclear.
• Microglial function in AD can be either protective or detrimental depending on disease stage.

Purpose of the Study:

• To characterize microglial responses to Aβ pathology using a novel 3D human induced pluripotent stem cell (iPSC)-derived neurosphere model.
• To investigate the impact of microglia on neuronal health and gene expression in the context of Aβ-induced amyloidosis.

Main Methods:

• Developed a 60-day 3D neurosphere model using iPSC-derived neurons and microglia.
• Induced amyloidosis with continuous synthetic oligomeric Aβ treatment.
• Monitored neuronal oxidative stress and calcium activity using roGFP1 and GCaMP6f sensors.
• Analyzed transcriptomic changes via single-nuclei RNA sequencing (snRNA-seq).

Main Results:

• Microglia infiltrated neurospheres and prevented neurotoxicity in mild Aβ exposure (3 weeks).
• Microglia failed to prevent neurotoxicity in severe Aβ exposure (5 weeks).
• snRNA-seq revealed microglia modulated oxidative stress genes and AD-associated genes (APOE, CLU, FTL) in astrocytes and neurons.
• Microglia showed enhanced Aβ clearance after anti-Aβ antibody treatment.

Conclusions:

• The 3D neurosphere model effectively mimics key Alzheimer's disease pathological features.
• Microglia exhibit neuroprotective properties in this model, potentially enhanced by antibody treatment.
• Microglia are critical in driving AD-associated transcriptomic changes under severe Aβ insult, highlighting their complex role and therapeutic potential.