Probing the Novel Roles of Neuromodulators in Alzheimer’s Disease

This project aims to investigate how neuromodulator systems lost early in Alzheimer’s disease regulate cholesterol metabolism in human cortical neurons, and to test whether restoring neuromodulatory input can rescue cholesterol, mitochondrial, and neuronal activity defects in stem cell-derived orga

This project will explore how brain chemicals like serotonin regulate cholesterol balance in nerve cells and how this goes wrong in Alzheimer’s disease. Using advanced stem cell models that mimic the human brain, we will study how loss of a key Alzheimer’s risk gene disrupts this regulation and whether boosting serotonin signaling can restore healthy function. Our goal is to uncover new ways to protect brain cells and slow disease progression.

This proposal is innovative in that it bridges two largely separate domains of Alzheimer’s research, the early vulnerability of neuromodulatory systems and the dysregulation of brain cholesterol metabolism, by testing whether the former mechanistically drives the latter in human neurons. We leverage novel human stem cell-derived assembloids, a modular platform that allows us to physically combine healthy and disease-carrying brain regions and isolate the contribution of long-range serotonergic input to cortical pathology, an experiment not feasible in conventional animal or 2D culture models. Together, this framework reframes neuromodulator loss not just as a driver of cognitive symptoms but

For the field, this study will establish a new mechanistic framework linking the early loss of neuromodulatory systems in Alzheimer’s disease to the breakdown of cholesterol homeostasis in cortical neurons, providing a unifying explanation for two long-standing but disconnected observations in AD pathophysiology. It will also deliver a versatile human assembloid platform that other researchers can adopt to study how long-range neuromodulatory inputs shape disease vulnerability across a range of neurodegenerative and neuropsychiatric conditions. For the general public, these findings could help link widely prescribed drugs such as SSRIs to AD pathogenesis, and point toward new therapeutic str