# The role of micro-RNA-33 in Tau pathology

> **NIH NIH F31** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $43,784

## Abstract

Project Summary/Abstract
Alzheimer’s Disease (AD) is the leading cause of dementia, and currently affects nearly 50 million people
worldwide. The pathological hallmarks of AD are the aggregation of amyloid-ß (Aß) plaques, the formation of
neurofibrillary tangles (NFT) comprising of aggregated hyperphosphorylated TAU protein, and increased
neuroinflammation. Despite AD being one of the most highly funded diseases by the NIH, there is a lack of
understanding in how these hallmarks contribute to disease progression. Furthermore, there have been no
disease modifying treatments developed for AD. Many of these failed therapeutics involved the singular
targeting of the pathological hallmarks of AD. Identifying targets within an overlapping pathway/mechanism
related to Aß, tau and chronic neuroinflammation could yield more promising results in terms of developing
therapeutics. Previously, it has been shown that reduction of micro-RNA-33 (miR-33) dramatically reduces Aß
levels in an amyloid mouse model. miR-33 regulates the expression of many genes relating to both cholesterol
homeostasis and inflammatory pathways. Intriguingly, neuronal cholesterol dysregulation and chronic
inflammation are implicated in tau pathology, independent of Aβ. The goal of this proposal is to understand the
functional consequences miR-33 deletion on tau pathology. To study the role of miR-33 deletion in tau
pathology, we will inject miR-33 wildtype or miR-33 knockout mice with an AAV expressing a pathogenic
human form of tau. We will then compare the extent of tau pathology between the wildtype and the miR-33
knockout mice. To elucidate the precise mechanisms in which miR-33 regulates tau pathology, we will
generate primary cell cultures from either miR-33 wildtype or miR-33 knockout mice. We will then transduce
these cells with AAV expressing pathogenic human tau to generate an in vitro Tauopathy model. The overall
hypothesis of this proposal is that deletion of miR-33 will ameliorate tau pathology. To achieve the goals
of this proposal, we will determine the effect of miR-33 deletion on inflammation and pathological changes in
tau, including hyperphosphorylation and formation of NFTs by employing western blot analysis,
immunohistochemistry (IHC), and ELISA based assays in our Tauopathy mouse model. Furthermore, we will
assess the effect of miR-33 deletion on the anxiety like behavior and deficits in learning and memory observed
in this Tauopathy mouse model. To determine the cell-type specific context of miR-33 reguation of tau
pathology, we will perform mass spectrometry on brain tissue from our mouse model to determine the effects
miR-33 deletion has on whole proteome changes. To determine the cell-type specific regulation of miR-33 on
tau pathology, we will generate neuronal and microglial in vitro Tauopathy models. We will utilize western blot
analysis, IHC, and ELISA based assays to determine changes in inflammatory response as well as
proteopathic changes in tau Upon co...

## Key facts

- **NIH application ID:** 10466097
- **Project number:** 1F31AG074673-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Mason Douglas Tate
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,784
- **Award type:** 1
- **Project period:** 2022-08-12 → 2024-08-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466097

## Citation

> US National Institutes of Health, RePORTER application 10466097, The role of micro-RNA-33 in Tau pathology (1F31AG074673-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10466097. Licensed CC0.

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