# Capturing the molecular complexity of Alzheimer's disease through the lens of RNA binding proteins

> **NIH NIH RF1** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $410,947

## Abstract

Neuritic plaques and neurofibrillary tangles are the hallmark pathologies of Alzheimer's disease (AD),
but the presence individual tangles or plaques is not sufficient to predict degeneration; 45% of the
elderly with plaques and tangles lack cognitive loss or dementia. We have recently identified a new
type of molecular pathology in AD that derives from the aggregation of RNA binding proteins (RBPs),
forming RNA-protein complexes, which are termed RNA granules. Microtubule associated protein tau
(MAPT) binds to RBPs, co-localizes with RBPs in RNA granules, and RBPs increase MAPT misfolding
/aggregation. Importantly, reducing the RBP TIA1 delays progression of tauopathy, despite increased
MAPT aggregation. We hypothesize that variation in the composition of MAPT complexes (soluble or
insoluble) and RNA granule complexes represent critical determinants of the molecular heterogeneity
of AD and other tauopathies, and identify particular pathways that uniquely contribute to each type of
disease. We will apply systems biology approaches that integrate information from proteomics and
RNA metabolism to identify key proteins in each complex that are associated with neurodegeneration,
and then test the roles of these proteins/genes experimentally. Throughout this proposal we will use
unbiased studies (e.g., proteomic and RNAseq) combined with the systems biology algorithms to
model context-dependent information flows to identify key molecular interactions and pathways
regulating pathology, neurodegeneration and neuroprotection. Aim 1 will determine whether the RBP
TIA1 directs the biochemical and functional properties of MAPT aggregation. We have discovered that
reducing the RBP TIA1 delays disease progression in PS19 P301S MAPT mice despite producing more
aggregation. We will elucidate the mechanisms by which TIA1 reduction produces neuroprotection
using both in vitro molecular studies, and use unbiased “omic” studies (mass spectrometry and
RNAseq). We will apply the systems biology algorithms to quantify key gene-gene interactions and
pathways, and identify those pathways that parallel the human condition. Aim 2 will determine how
MAPT and RBP complexes vary with cognitive decline in humans. We will use mass spectrometry and
RNAseq to determine how the composition of complexes of MAPT, TIA1 and other key RBPs varies
among human cases exhibiting neuritic plaques and neurofibrillary tangles with or without cognitive
decline. Aim 3 will determine whether RBPs direct the strain of MAPT and resulting pathologies that
are propagated in vitro and in vivo. We will characterize propagation of tauopathy for MAPT
aggregates from PS19, PS19xTIA1+/--mice, as well as human cases exhibiting MAPT pathology with
and without cognitive decline. The resulting mice will be analyzed as described in Aim 1.

## Key facts

- **NIH application ID:** 10249415
- **Project number:** 3RF1AG056318-01A1S1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Hu Li
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,947
- **Award type:** 3
- **Project period:** 2018-06-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249415

## Citation

> US National Institutes of Health, RePORTER application 10249415, Capturing the molecular complexity of Alzheimer's disease through the lens of RNA binding proteins (3RF1AG056318-01A1S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249415. Licensed CC0.

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