Boston University
Pharmacology
Dr. Lulu Jiang is a Research Assistant Professor in the Pharmacology & Experimental Therapeutics department at the Boston University School of Medicine. Dr. Jiang’s PhD training was from the National Institute of Environmental Health Sciences (NIEHS) in USA and MD training from Shandong University in China. She was a Postdoc Fellow in the Laboratory of Neurodegeneration mentored by Dr. Benjamin Wolozin. Her previous work demonstrated that propagated tau oligomers (but not tau fibrils) induce pathological changes in RNA metabolism and neurodegeneration. Upon that, Dr. Jiang developed an optogenetic system for controlling tau aggregation, which brought in a seminal discovery that tau oligomerization drives the accumulation of RNA binding protein HNRNPA2B1 and N6-methyladenosine modified transcripts in the aggregated tau complex. Dr. Jiang has also lead on the generation of human 3D iPSC M/AstAD based models of AD for the exploration of molecular mechanism and drug screening. Her research interests include: 1) Protein-Protein and Protein-RNA interactions in AD and related dementia; 2) Molecular mechanism of Tau prion-like propagation in Braak stages of AD; 3) Neuron-glia interactions in pathogenesis of AD and PD; 4) iPSC-induced 3D brain organoid models of neurodegenerative diseases and precision medicine; 5) Development of novel therapeutics for neurodegenerative diseases.

Presenter of 1 Presentation

GENERATION OF A PATIENT IPSC-INDUCED 3D SPHEROID MODEL TO STUDY PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE AND INVESTIGATE NOVEL THERAPEUTICS

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
08:30 AM - 10:30 AM
Room
ONSITE: 131-132
Lecture Time
09:15 AM - 09:30 AM

Abstract

Aims

Exploration of the pathophysiology of Alzheimer’s disease (AD) has been hampered by lack of systems that accurately recapitulate full profile of disease progression. We have developed a 3-dimentional assembloid model with iPSC induced neurons, astrocyte and microglia derived from AD subjects to investigate the pathophysiology, protein-protein interactions, cellular mechanism and interventional strategies for AD.

Methods

Lines of APP V717I iPSC and isogenic controls were differentiated into neuronal, astrocytic and microglial progenitor cells in 2D culture, and the neuronal cells were seeded with tau oligomers (oTau). The three cell types of progenitor cells were then mixed together to generate 3D Microglia-Astrocyte-Neuronal spheroids (MAstAD).

Results

Analysis of the MAstAD cultures after 1-3 weeks of culture revealed abundant b-amyloid deposition, tau pathology, neurodegeneration, astrogliosis and microglial activation. Immunofluorescence labeling demonstrated abundant Ab deposits (observed by Thiazine red or 4G8 antibody labeling), tau phosphorylation and aggregation, microglial activation (Iba1 labeling and TNF-a- secretion) and neurodegeneration quantified using FluoroJade B, cleaved caspase 3 and LDH measurements. APP V717I mutation and oTau seeding synergistically exacerbated all the phenotypes. Coincident single cell RNA sequencing and mass spectrometry were also performed to explore the cellular and molecular signal pathways in the disease progression.

Conclusions

We have generated a novel 3D assembloid model of AD, which we term MAstAD. The MAstAD system recapitulates many features of AD pathology including microglia/astrocyte gliosis, Ab and tau pathology, and neurodegeneration. This innovative AD model offers an advanced platform to study the cellular and molecular mechanisms of disease progression and develop effective therapeutic strategies for AD.

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