# MiR-193a-5p as a Regulator of Intersectin1-short and Clathrin-Mediated Endocytosis in Alzheimer's Disease.

> **NIH NIH R36** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $49,503

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the development of
amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Currently, the pathogenesis underlying AD is
unclear and there are no reliable tools to detect early changes in the brain. Studies in the Saugstad lab
revealed a specific set of microRNA (miRNA) biomarkers that are decreased in cerebrospinal fluid (CSF), and
which can classify AD patients from neurologically normal controls. MiRNAs regulate post-transcriptional gene
expression via complementary binding to sequences in mRNA that in turn regulate translation and expression
of the resulting protein. However, there is a knowledge gap regarding which mRNAs are targeted and
regulated by the AD CSF miRNAs and how these target proteins may contribute to AD pathophysiology. To
address this gap, I developed a bioinformatics pipeline to predict mRNA targets of the AD CSF miRNAs, and
identified Intersectin1-short (ITSN1-s) as a protein targeted by the AD CSF miRNA, miR-193a-5p. Immunoblot
analysis of human post mortem hippocampus showed significant increases in ITSN1-s protein in AD relative to
control. However, as ITSN1-s is expressed in multiple brain cell types, further studies that determine the
specific cell type(s) with increased ITSN1-s expression in AD are needed to examine potential mechanisms
underlying AD. Published studies report that ITSN-s is expressed in astrocytes and microglia, with low
expression in neurons, and that ITSN1-s functions to reduce clathrin-mediated endocytosis (CME). Microglia
have been shown to uptake fibrillar Aβ through a clathrin-mediated mechanism, and CME disruption in AD has
been linked to reduced Aβ clearance in neurons. However, it is not known whether ITSN1-s in microglia
contributes to this pathophysiology in AD. This proposal will assess the regulatory role of miR-193a-5p on
ITSN1-s and its functional significance in CME and AD. In order to accomplish this, I propose the following
aims: 1. establish the cellular expression of miR-193-a-5p and ITSN1-s in AD microglia and neurons; 2.
investigate the interaction between miR-193a-5p and ITSN1-s mRNA and the effects on ITSN1-protein
expression in vitro and in vivo; and 3. determine the role of miR-193a-5p levels on CME and Aβ uptake in AD
microglia. Ultimately, these studies will provide a deeper understanding of ITSN1-s regulation in AD and how
this may contribute to AD pathology. In addition, this framework can be used in future studies to evaluate the
biological consequences of circulating miRNA biomarkers in AD.

## Key facts

- **NIH application ID:** 10288636
- **Project number:** 1R36AG073792-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Sierra Smith
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $49,503
- **Award type:** 1
- **Project period:** 2021-09-05 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288636

## Citation

> US National Institutes of Health, RePORTER application 10288636, MiR-193a-5p as a Regulator of Intersectin1-short and Clathrin-Mediated Endocytosis in Alzheimer's Disease. (1R36AG073792-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10288636. Licensed CC0.

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