GBF1 inhibition reduces amyloid-beta levels in viable human postmortem Alzheimer's disease cortical explant and cortical organoid models

Title : GBF1 inhibition reduces amyloid-beta levels in viable human postmortem Alzheimer's disease cortical explant and cortical organoid models

Abstract:

Aging is a leading risk factor for the onset and progression of Alzheimer’s disease, characterized by key histopathological features such as amyloid-beta aggregation and Tau protein tangles. Amyloid-beta species are generated through the proteolytic cleavage of Amyloid Precursor Protein (APP), a process that has drawn significant attention to identify therapeutic interventions that modulate APP trafficking. One such protein, Golgi Brefeldin A resistance factor (GBF1), has been implicated in regulating APP trafficking, potentially before amyloid-beta generation. To investigate GBF1’s role in Alzheimer’s disease pathogenesis, we utilized translational human models, including ex vivo electrophysiologically active postmortem cortices from Alzheimer’s disease donors and in vitro cortical organoids. Machine-learning based analysis of human brain single-cell RNA sequencing data revealed dysregulation of GBF1 in Alzheimer’s disease. We then performed histological analysis of rapid autopsy human cortical samples and human cortical organoids, revealing pathological alterations in GBF1 associated with amyloid-beta plaques in Alzheimer’s disease models. Functional studies using a GBF1 inhibitor demonstrated significant reductions in amyloid-beta levels in both human cortical tissues and cortical organoids. Taken together, the single-cell analysis, rapid autopsies, cortical organoids, neuropathological, and functional findings suggest that GBF1 plays a critical role in amyloidogenic pathways and may serve as a promising therapeutic target for reducing amyloid-beta production in Alzheimer’s disease.

Biography:

For over a decade, Dr. Sean Miller has been studying the underlying pathophysiology of age-related neurodegenerative disorders. Dr. Miller performed his previous research at institutions such as Drexel University, Harvard Medical School, Massachusetts General Hospital, the Johns Hopkins University School of Medicine, Stanford University School of Medicine, and is now serving as junior research faculty at Yale School of Medicine. Dr. Miller comes highly cited in the field of neurodegenerative proteinopathies such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. With well over 3,000 citations from publications in journals such as Science, Science Advances, Nature, Nature Neuroscience, and Neuron, he continues to push the boundaries in resolving neurodegeneration.