# Linking tau proteostasis with neuronal activity in FTD

> **NIH NIH U54** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $2,043,639

## Abstract

ABSTRACT — OVERALL COMPONENT
Neurodegenerative tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration
with tau inclusions (FTLD-tau), are characterized by tau inclusions of hyperphosphorylated tau. However,
which tau species are pathogenic and how they induce neuronal dysfunction remain elusive. We hypothesize
that there is a crosstalk between tau proteostasis imbalance, in the form of intracellular accumulation and
intercellular spread, and neuronal dysfunction. Our vision statement is: Linking tau proteostasis with
neuronal activity in FTD. We propose to use a combination of unbiased discovery and focused hypothesis-
driven approaches to dissect the mechanistic connection. The Center, composed of three projects (P1–P3)
and five cores (MS, CRISPR, Human, Data and Admin), aims at addressing the following fundamental
questions in tau pathogenesis. In Specific Aim 1, we will address what causes tau to accumulate and spread
in FTD. P1 and P3 will work together with MS core to dissect whether aberrant post-translational modifications
(PTMs) are critically involved in modulating tau's failure to be degraded and subsequent release. P1, P2 and
P3 will work together with CRISPR core to dissect the uptake and seeding mechanisms, using a combination
of hypothesis-driven candidate approaches and genome-wide CRISPRi/a library screening. P1, P2 and P3 will
work together with the Human core to validate the findings from iPSC neurons in human tissues. In Specific
Aim 2, we will determine how tau proteostasis imbalance induces neuronal dysfunction. Despite large amount
of evidence supporting the accumulation and spread of tau pathology in animal models and in cultured cells,
little is known about the mechanisms behind this toxicity and their direct impact on neuronal/synaptic function
in human neurons. P1 and P2 will work together to define the effects of FTD mutations on human neuronal
activity both at the single-cell and network levels using whole-cell patch clamp and multi-electrode array
(MEA), respectively. P3 will work with P1 and P2 to examine if altered autophagy affects neuronal activity. P1,
P2 and the CRISPR core will work together to examine the functional effects of tau oligomerization. In Specific
Aim 3, we will examine how neuronal activity modulates tau proteostasis. Both in vitro and in vivo studies
showed that the release of tau is activity-dependent, supporting a feedback mechanism by which aberrant
neuronal activity further alters tau proteostasis. P1 will work with the MS and CRISPR cores to dissect the
mechanisms underlying the activity-dependent tau release. P1 and P2 will work synergistically to address if
and how neuronal activity could affect the uptake (P2) or seeding (P1) of pathogenic tau. P3 will work with P1
and P2 to determine how altering neuronal activity modulates different autophagic pathways. In summary, the
Center is strategically structured to maximize conceptual and technological synergies, f...

## Key facts

- **NIH application ID:** 10011925
- **Project number:** 5U54NS100717-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Li Gan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,043,639
- **Award type:** 5
- **Project period:** 2016-09-30 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011925

## Citation

> US National Institutes of Health, RePORTER application 10011925, Linking tau proteostasis with neuronal activity in FTD (5U54NS100717-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10011925. Licensed CC0.

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