# The molecular mechanism of PICALM-dependent endosomal trafficking

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $206,250

## Abstract

ABSTRACT
Dysregulation of endocytosis and endosomal trafficking pathways contributes to the pathogenesis of Alzheimer’s
disease and related dementia (ADRD). Beside controlling amyloid precursor processing and β-amyloid (Aβ)
production in neuronal cells, endocytosis and endosomal trafficking pathways also exist in brain endothelial cells
and govern the Aβ clearance cross Blood-brain barrier (BBB) through receptor mediated transport (RMT). A
properly functioning RMT is highly selective due to the spatial distribution of the receptors and specific interaction
with their ligands, which ensures the exclusive entry of essential peptides and proteins into the brain and effective
clearance of toxic waste from brain to blood in maintaining CNS health and functions. However, our
understanding of this unique RMT system within the BBB remains very limited.
RMT is tightly regulated by products of AD risk genes, such as Apolipoprotein E and phosphatidylinositol-binding
clathrin assembly protein (PICALM). PICALM, a highly validated risk gene for Alzheimer’s disease, is also an
endosomal protein and a key component of the RMT machinery at the BBB. PICALM controls the RMT
transcytosis across the BBB by facilitating the clathrin-mediated endocytosis and intracellular trafficking of cell
surface receptors and their ligands. PICALM deficiency in mice results in defected transferrin trafficking and
diminished brain clearance of Alzheimer’s amyloid-β peptides (Aβ) across the BBB. Therefore, delineate the
molecular mechanism of PICALM-mediated transcytosis events offers new opportunities in advancing our
understanding of the BBB RMT system, as well as its role in AD pathogenesis. Through in-depth analysis of
PICALM’s interactome and functional target validations using an in vitro BBB model, we found that PICALM
interacting mitotic regulator (PIMREG) is a novel functional partner for PICALM in the brain endothelial cells and
is required for the later steps of RMT transcytosis. Therefore, we hypothesize that PIMREG is an integral
component of the RMT machinery, and teams up with PICALM and other proteins in controlling the intracellular
trafficking and transcytosis of cargo vesicles, which is essential for brain homeostasis and Aβ clearance.
To test our hypothesis, we propose to determine the function of PICALM-PIMREG complex in controlling
endosomal trafficking events in primary brain endothelial cells (AIM 1), understand the role PIMREG in regulating
the PICALM-mediated RMT transcytosis of different ligands across the in vitro BBB model (AIM 2), and probe
PIMREG’s function in vivo for PICALM-dependent Aβ clearance across the BBB using antisense
oligonucleotides (ASOs) (AIM 3). We expect to generate unique new insights into the biology and molecular
mechanism of RMT transcytosis at the BBB, and provide first-hand evidence of a novel component of PICALM-
dependent Aβ clearance across the BBB, which will expand our understanding of RMT and its roles in BBB
dysfunction and...

## Key facts

- **NIH application ID:** 10017851
- **Project number:** 5R21AG066090-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Zhen Zhao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $206,250
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017851

## Citation

> US National Institutes of Health, RePORTER application 10017851, The molecular mechanism of PICALM-dependent endosomal trafficking (5R21AG066090-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10017851. Licensed CC0.

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