# Regulation of LC3-associated endocytosis and neuroinflammation

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2024 · $362,538

## Abstract

PROJECT SUMMARY
Neuroinflammation is a key component to the establishment and progression of
neurodegenerative diseases including Alzheimer’s Disease (AD). We recently identified a novel
pathway called LC3-associated endocytosis (LANDO) and found it is important for mitigating
neuroinflammation and neurodegeneration in a model of AD. We have robust preliminary
evidence demonstrating that LANDO functions to suppress inflammatory signaling in microglia,
the resident innate immune cells in the brain. Activation of LANDO facilitates the recycling of
receptors that recognize β-amyloid, a contributor to AD pathology. Abrogation of LANDO results
in a severe exacerbation of all markers of AD including not only β-amyloid deposition, but
increased tau pathology, neuronal loss, and memory impairment. Furthermore, targeting
inflammatory signaling in LANDO-deficiency is able to almost fully inhibit neuronal death while
restoring microglial function and improving memory. However, the mechanisms that control
LANDO in microglia and ultimately link LANDO to inflammatory signaling are unknown. We
provide convincing evidence that components of retromer machinery including VPS35 and
Rab11b are essential for LANDO, however are dispensable for related pathways including
autophagy and LC3-associated phagocytosis. Additionally, we provide evidence that suggests
LANDO alters inflammatory activation through restriction of inflammasome assembly and
decreases pro-inflammatory reactive oxygen species levels. We further provide data that
suggests abrogation of upstream LANDO activation and its role in inflammatory mechanisms
leads to diverse programs of neuronal cell death including putative roles for the necroptotic
machinery in both death and inflammation. We propose to use a variety of novel animal models
and assays we have established to evaluate LANDO regulation, inflammation, and neuronal death
at both the molecular and physiological levels in AD. These studies will provide new opportunities
for the manipulation and development of therapeutic methodologies for AD in addition to
increasing our understanding of this complex, multifaceted biological system.

## Key facts

- **NIH application ID:** 10756137
- **Project number:** 5R01NS124783-03
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Bradlee L Heckmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $362,538
- **Award type:** 5
- **Project period:** 2021-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756137

## Citation

> US National Institutes of Health, RePORTER application 10756137, Regulation of LC3-associated endocytosis and neuroinflammation (5R01NS124783-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10756137. Licensed CC0.

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