Neurobiology Laboratory of Masato Maesako, PhD

Overview

The Maesako Laboratory explores the molecular mechanisms that are associated with neuronal loss in Alzheimer’s disease and other neurodegenerative diseases. The research team employs cell biology techniques and state-of-the-art microscopy-based imaging methods and is eager to facilitate the successful transition of scientific findings from basic research to clinical applications.

Research projects

FRET microscopy to better understand gamma-secretase biology

A change in gamma-secretase activity is linked to essential biological events as well as to the progression of many diseases that include Alzheimer’s disease. However, not much is known about how gamma-secretase activity is spatiotemporally regulated in cells. One of the limitations is the lack of tools to directly monitor the dynamic behavior of g-secretase in intact/live cells. Our research team has successfully developed and validated the Förster Resonance Energy Transfer (FRET)-based biosensors that enable, for the first time, quantitative monitoring of endogenous gamma-secretase activity in live cells longitudinally, on a cell-by-cell basis. Using these FRET biosensors, we showed that -secretase activity is heterogeneously regulated among live neurons in vitro and in vivo. Our current research aims to address the exact consequences of this
cell-to-cell heterogeneity.

gamma-Secretase in the endo-lysosomal system

Alzheimer’s disease genetics indicate that APP C99 cleavage by gamma-secretase is essential in disease pathogenesis. However, exactly where inside the neurons this crucial cleavage occurs remains unclear. By using state-of-the-art molecular imaging assays and our unique molecular biosensors, we have directly visualized that C99 is predominantly processed by gamma-secretase in the endo-lysosomal compartments in live/intact neurons. Moreover, we showed that Abeta is enriched in the same subcellular loci. Surprisingly, our recent research suggests that endo-lysosome membrane is more vulnerable to leakage in APP or gamma-secretase deficient cells.

Molecular factors linked to neuronal vulnerability and death

It is well established that some individuals can tolerate robust amounts of Alzheimer’s pathological lesions without experiencing clinical symptoms and neuronal loss. This clearly suggests that not only eliminating toxic factors that cause neuronal death, but also promoting neuronal resilience could be promising therapeutic strategies for the disease. Nevertheless, the mechanisms that regulate neuronal vulnerability and resilience are poorly understood. Our recent research points to gamma-secretase and the endo-lysosomal system as important upstream regulators. Moreover, our research team has developed a unique cell labeling and sorting method that enables the physical separation and isolation of selectively vulnerable vs. resilient neurons in culture, providing a rigorous experimental framework for exploring potential mechanisms and the consequences of selective neuronal vulnerability.

Publications

https://www.ncbi.nlm.nih.gov/pubmed/?term=maesako+masato

Open Positions

Applicants for Postdoctral Fellow, Research Technician, and Internship positions should contact the principal investigator, Masato Maesako PhD, directly (MMAESAKO@mgh.harvard.edu).