Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Investigating cellular phenotypes in induced pluripotent stem cell (iPSC)-derived cortical neurons from sporadic Alzheimer's disease (sAD) patients.
• Comparing these cellular phenotypes with available clinical data from the originating patients.

Purpose of the Study:

• To assess the resilience and vulnerability of sAD patient-derived neurons to Amyloid Beta (AB) insult.
• To examine transcriptomic differences between patient lines following AB exposure.

Main Methods:

• Utilized iPSC lines from 14 sAD patients with extensive clinical data (PET, MRI, cognitive tests, CSF).
• Differentiated iPSCs into cortical neurons using a doxycycline-inducible Ngn2 system.
• Treated neurons with AB oligomers and performed bulk RNA-sequencing and downstream analysis.

Main Results:

• Demonstrated a spectrum of vulnerability to AB insult, with some patient lines showing up to 80% neurite loss while others had minimal loss (10-12%).
• Observed correlation between cellular vulnerability and clinical measures, such as hippocampal volume.
• Identified that AB oligomer treatment significantly perturbs lipid synthesis, metabolism, synapse formation, neuronal migration, and proteasomal pathways.

Conclusions:

• iPSC-derived neurons exhibit inter-individual variability in response to AB insult.
• This cellular vulnerability spectrum correlates with clinical patient measures, like hippocampal volume.
• AB induces significant transcriptomic changes in cortical neurons, highlighting lipid metabolism and proteasomal pathways.