# Roles of reticulon proteins in neurodegenerative disorders

> **NIH NIH RF1** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $3,031,508

## Abstract

Alzheimer’s disease (AD) is characterized by the presence of extracellular neuritic plaques and
intraneuronal neurofibrillary tangles. In addition to amyloid plaques and neurofibrillary tangles, the
presence of dystrophic neurites (DNs), referring to aberrant neuritic sprouting as well as swollen
dendrites and/or axons, is known as one pathological feature in surrounding amyloid plaques on AD
postmortem brains, and has been shown to correlate with cognitive dysfunctions in AD. With the
increasing number of failures in clinical trials that target the formation of amyloid deposition, AD
treatment is recognized to be extremely challenging. This study aims to explore the approach for
preventing or reducing DNs. We have previously demonstrated that reticulon proteins, mainly RTN3 but
not RTN1, are massively accumulated in DNs in surrounding neuritic but not diffuse amyloid plaques.
RTN3+ DNs contain mainly clustered tubular endoplasmic reticulum (ER). To build around this finding,
we have recently discovered through our various morphological characterizations that ATG9A‐positive
DNs (ATG9A+ DNs) form near the core plaques while RTN3+ DNs form subsequently and can surround
ATG9A+ DNs. ATG9A is a critical molecule required not only for pre‐autophagosome formation but also
for autophagosome elongation and maturation. DNs, enriched with multibody vesicles and marked by
the autophagy protein LC3 and RAB7 or ubiquitin, are usually distributed relatively farthest from the
core amyloid plaque and develop the latest in our temporal study. In light of growing knowledge in this
area, we propose to advance our study further by testing the hypothesis in this renewal application that
aging and amyloid deposition induces ATG9A‐mediated abnormal trafficking and subsequent tubular ER
clustering and autophagic dysfunctions in AD brains. Two specific aims are proposed to test this
hypothesis: 1) Aim 1 is to investigate the effects of amyloid pathology on ATG9A trafficking and the
underlying mechanism; 2) Aim 2 is to determine the role of microglia in mediating growth of dystrophic
neurites in surrounding amyloid plaques. Overall, this renewal proposal has a set of readily achievable
experiments that focus on the growth of various form of DNs and functional relationship between
reticulon proteins and ATG9A in AD pathogenesis. We will also explore molecular targets for reducing or
preventing formation of DNs for the ultimate purpose of improving cognitive functions. Such a study will
yield critical knowledge that may guide therapeutic applications for decreasing DN formation and
cognitive dysfunction in AD patients.

## Key facts

- **NIH application ID:** 10050837
- **Project number:** 2RF1AG025493-16
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** RIQIANG YAN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,031,508
- **Award type:** 2
- **Project period:** 2005-01-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050837

## Citation

> US National Institutes of Health, RePORTER application 10050837, Roles of reticulon proteins in neurodegenerative disorders (2RF1AG025493-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10050837. Licensed CC0.

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