# Novel role of TFEB in ADAM10 potentiation and proliferation of neural precursor cells relevant to Alzheimer's disease

> **NIH NIH R21** · FLORIDA INTERNATIONAL UNIVERSITY · 2020 · $221,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a complex and a highly heterogeneous disease characterized by the deposition of
extracellular and intracellular protein deposits. Accumulating data suggest that autophagy-lysosome pathway
(ALP) is severely compromised in human AD and activation of ALP is likely to have therapeutic potential for
combating neurodegeneration in the AD. It was recently discovered that the transcription factor EB (TFEB), a
basic helix-loop-helix transcription factor is a master regulator of the entire ALP. Interestingly, we found the
selective loss of nuclear TFEB protein levels in Braak stage-dependent manner in AD patients and that
exposure of primary neurons to Aβ oligomers also markedly reduced TFEB immunoreactivity. So far multiple
laboratories around the world have repeatedly confirmed the role of TFEB in markedly reducing the protein
aggregates in the APP/PS1 as well as tauopathy models using viral vectors for TFEB expression. By
generating flag-TFEB transgenic mice for the first time, we showed that TFEB expression significantly reduces
hyperphosphorylated tau in the P301S model of tauopathy.
 Since TFEB has demonstrated promising effects in models of AD, our continued investigations made a
surprising discovery that TFEB potentiates the α-secretase ADAM10 expression and sAPPα generation in
multiple cell lines and primary neurons. More importantly, here for the first time we show that TFEB expression
increases mature ADAM10 protein levels in vivo. Both sAPPα and ADAM10 have many beneficial properties
including neuroprotection, neurite extension, prevention of dendritic degeneration, memory enhancement,
inhibition of tau phosphorylation and increased trophic support. More importantly, both ADAM10 and sAPPα
have shown indisputable role in the proliferation of neural precursor cells (NPCs) and adult neurogenesis. The
failure of most AD clinical trials may suggest that mere reductions in Aβ levels may be insufficient to combat
AD and that a mechanism to increase additional benefits may be needed. Therefore in this proposal by using
our newly generated flag-TFEB mice we want to assess whether TFEB can mitigate the age-associated
decline in the number of NPCs and neurogenesis by quantifying BrdU+, NeuN+, DCX+ and their double
positives.in the subventricular zone and subgranular zone by measuring spatial memory, motor activity,
ADAM10 activity, and sAPPα levels. More crucially, we have also designed experiments to identify the
mechanistic basis for TFEB’s role in neurogenesis. We will also test whether TFEB can provide significant
protection against excitotoxicity and Aβ oligomers in the organotypic cultures. Using antibodies against
ADAM10/sAPPα, we will also address whether ADAM10/sAPPα are responsible for neuroprotection. If positive
results are obtained, it may lead to the initiation of a new line of research on TFEB and its pathway on the role
of neurogenesis in models of AD and ultimately TFEB may turn out to ...

## Key facts

- **NIH application ID:** 9981582
- **Project number:** 5R21AG060299-02
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Madepalli Krishnappa Lakshmana
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $221,250
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981582

## Citation

> US National Institutes of Health, RePORTER application 9981582, Novel role of TFEB in ADAM10 potentiation and proliferation of neural precursor cells relevant to Alzheimer's disease (5R21AG060299-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9981582. Licensed CC0.

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