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 A? 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 ?-secretase ADAM10 expression and sAPP? 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 sAPP? 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 sAPP? 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 A? 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 sAPP? 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 A? oligomers in the organotypic cultures. Using antibodies against ADAM10/sAPP?, we will also address whether ADAM10/sAPP? 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 be excellent therapeutic target for AD.

Public Health Relevance

Alzheimer?s disease is a chronic neurological disorder of elderly characterized by progressive neurodegeneration due to increased levels of toxic and reduced levels of protective factors. Because of failure of house-keeping functions, toxic protein aggregates accumulate in the neurons, which is responsible for loss of neurons and memory. Here we want to test whether a gene that increases house-keeping functions could also make new neurons and protect neurons from toxic proteins thereby prevent loss of neuronal connections and cognition in a model of Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG060299-01A1
Application #
9824958
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Opanashuk, Lisa A
Project Start
2019-08-01
Project End
2021-04-30
Budget Start
2019-08-01
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199