# Exploring the Pathophysiology of AD and ADRDs with 3D Asteroid Models

> **NIH NIH R56** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $916,247

## Abstract

This proposal presents a powerful new approach for modeling Alzheimer's Disease (AD) and AD-related
diseases (ADRD), which enables discovery of important conceptual advances in our understanding of disease
mechanisms. We use mixed cultures of human neurons and astrocytes developed from iPSCs from APP717V
and isogenic control subjects. These are combined together into in 3D organoids, termed “asteroids”. Exposing
the asteroids to propagated tau oligomers (oTau) causes the neurons develop tau pathology and
neurodegeneration, creating a novel model for AD and ADRD, termed AstAD. The AstADs rapidly and
progressively develop many components tauopathy, including oligomeric tau, phospho-tau, misfolded tau,
fibrillar tau and neurodegeneration. Our studies with the AstAD model reveal that oTau disrupts ribosomal
biology, selectively changing levels of key ribosomal proteins known to exert non-ribosomal functions directed
at regulating the transcription factor HSF1, stress granules and the p53 pathway. These actions of oTau appear
to induce of a harmful dysfunctional network of heat shock proteins (HSPs) and p53 mediated activation of cell
death. However, selective dissociation of dysfunctional HSP complexes with the HSP90 inhibitor PU-H71,
elicits a surprising, powerful reduction oTau pathology and neurodegeneration. Dysregulation of ribosomal
protein levels has been observed in proteomic studies of AD, but the significance of ribosomal dysregulation
has never been questioned. Our observations lead to the hypothesis that oTau dysregulates ribosomal biology
in AstAD, producing deleterious patterns of ribosomal protein and HSP expression We will use the AstAD
model to determine how ribosomal dysregulation induced by Aβ, oTau or Aβ/oTau affects neurons and
astrocytes. We will also use the AstAD cultures to explore functions of neuron/glial interactions in disease, and
determine how protective strategies directed against neurons, glia or both provide resilience. Aim 1 will
determine the pattern of physiology, pathology and gene expression produced by Aβ, oTau, fibrillar tau or
Aβ/oTau. We will examine the biology of ribosomes, HSPs and RNA translation in the AstAD model, as well
as characterize key pathologies associated with AD and ADRD. Aim 2 will elucidate the complex biology of
tauopathies among different types of human AD and ADRD cases by examining effects on the physiological,
pathological and transcriptional responses in the AstAD cultures. We will induce neuropathology in AstAD by
exposure to brain lysate, oTau or fibrillar tau produced from different types of tauopathies (AD, FTD-tau, PSP,
CBD and PART) as well as comparison to FTD-TDP, which does not exhibit Aβ or tau pathology. Aim 3 will
determine the roles of key ribosomal and HSPs in neurons or glia during the pathological response to Aβ and
oTau. We will knockdown or over-express oTau-responsive ribosomal or HSP transcripts in neurons and/or
astrocytes. We will then determine the patterns of p...

## Key facts

- **NIH application ID:** 10459727
- **Project number:** 1R56AG074591-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Christine Cheng
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $916,247
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459727

## Citation

> US National Institutes of Health, RePORTER application 10459727, Exploring the Pathophysiology of AD and ADRDs with 3D Asteroid Models (1R56AG074591-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459727. Licensed CC0.

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