Novel Small Molecule Approach to Reduce ABO Build-Up in Alzheimer's Disease
Session Number
2
Advisor(s)
Raghad Nowar, Kirsten Viola, William Klein, Northwestern University, Klein Lab
Location
A123
Discipline
Medical and Health Sciences
Start Date
15-4-2026 11:10 AM
End Date
15-4-2026 11:55 AM
Abstract
A hallmark of Neurodegenerative diseases is protein aggregation. Aggregates of different proteins can lead to brain damage and loss of nerve cells. The 1988 Amyloid-β Oligomer hypothesis proposes that these soluble, ligand-like AβOs instigate brain damage that leads to Alzheimer’s. The Klein lab observations of fibril-free synthetic preparations of AβOs being potent neurotoxins show that they could rapidly inhibit long-term potentiation and overtime caused nerve cell death. NU-9, a small molecule inhibitor of toxic protein build-up impacts AβOs in AD cell models. Recent work from Klein lab showed its effect involves autophagy pathways in neuronal cells. Targeting those neurotoxins, we will investigate novel NU-9 derivatives to determine their efficacy and similarity to NU-9 and the positive control, Torin-1, a potent autophagy inducer. We will use cell-permeable live-cell dyes, that selectively label autophagosomes with quantitative fluorescence plate-reader assays to see if there is an increase of vesicle abundance based on fluorescence readings while examining how differences in lipophilicity and cell permeability of the novel analogs relate to their activity.
Novel Small Molecule Approach to Reduce ABO Build-Up in Alzheimer's Disease
A123
A hallmark of Neurodegenerative diseases is protein aggregation. Aggregates of different proteins can lead to brain damage and loss of nerve cells. The 1988 Amyloid-β Oligomer hypothesis proposes that these soluble, ligand-like AβOs instigate brain damage that leads to Alzheimer’s. The Klein lab observations of fibril-free synthetic preparations of AβOs being potent neurotoxins show that they could rapidly inhibit long-term potentiation and overtime caused nerve cell death. NU-9, a small molecule inhibitor of toxic protein build-up impacts AβOs in AD cell models. Recent work from Klein lab showed its effect involves autophagy pathways in neuronal cells. Targeting those neurotoxins, we will investigate novel NU-9 derivatives to determine their efficacy and similarity to NU-9 and the positive control, Torin-1, a potent autophagy inducer. We will use cell-permeable live-cell dyes, that selectively label autophagosomes with quantitative fluorescence plate-reader assays to see if there is an increase of vesicle abundance based on fluorescence readings while examining how differences in lipophilicity and cell permeability of the novel analogs relate to their activity.