Ju-Hyun Lee, PhD

My laboratory has been deeply engaged in investigating the autophagy-lysosomal pathway (ALP) and endosomal-lysosomal system alterations in the context of neurodegeneration, using both in vitro and in vivo Alzheimer’s disease (AD) models, as well as postmortem human AD brain tissue. At the cellular level, we focus on identifying early changes in lysosomal acidification (pH) in neurons that contribute to the onset and progression of AD. Our studies also explore how disruptions in autophagy—one of the cell’s key surveillance and clearance systems—underlie functional decline in the AD brain.

Our work is yielding critical insights into the in vivo regulation of the ALP in neurons and holds exceptional promise for unraveling how its dysfunction drives amyloid pathology in AD. These findings also open new avenues for the development of ALP-targeted therapeutics, addressing an urgent need in the field of ALP-related neurodegeneration.

In recent years, discoveries from our group reveal that ALP dysfunction emerges at remarkably early stages of AD—well before extracellular amyloid-β (Aβ) plaques are detectable. Notably, we observed defects in autolysosomal acidification as early as five months of age in AD mouse models—more than four months prior to Aβ plaque deposition—and preceding the appearance of neuritic plaques and neurofibrillary tangles in Brodmann areas 9/10 during early-stage late-onset AD (LOAD). In both postmortem human LOAD tissue and multiple transgenic AD mouse models, we identified a novel neuropathological phenotype, termed PANTHOS, marked by impaired autolysosome acidification, severe autophagic stress, and intraneuronal Aβ accumulation. Strikingly, neurons exhibiting PANTHOS morphology appear to evolve directly into a subset of extracellular neuritic plaques, challenging the prevailing view that plaques originate solely through extracellular processes and instead suggesting a neuron-intrinsic origin. This discovery underscores the urgent need to understand how ALP dysfunction contributes to subtype-specific neuronal vulnerabilities in AD.

Second line of research, we are investigating whether certain neuronal subpopulations are more susceptible to ALP dysfunction and consequently more prone to amyloid plaque formation. Selective neuronal vulnerability is a hallmark of AD, with excitatory neurons in the neocortex exhibiting heightened susceptibility. Although molecular patterns of vulnerability have been described, the mechanisms driving these cell type–specific differences remain poorly understood. Given the essential role of the ALP in maintaining neuronal proteostasis, its dysfunction represents a compelling mechanistic link to this selective vulnerability.