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Updated: Apr 12, 2026
Author Spotlight: A Personalized Approach Towards Investigating Alzheimer's Disease Using an In Vitro Blood-Brain Barrier Model
Published on: October 20, 2023
Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance
Zhen Zhao1, Abhay P Sagare1, Qingyi Ma1
1Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Abstract:
PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided Aβ trafficking to Rab5 and Rab11, leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance, which has implications for Aβ brain homeostasis and clearance therapy.
Insights
Reduced PICALM expression in Alzheimer's disease (AD) impairs amyloid-beta (Aβ) clearance across the blood-brain barrier (BBB). Restoring PICALM enhances Aβ transport, offering potential for new AD therapies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- PICALM is a validated genetic risk factor for Alzheimer's disease (AD).
- Reduced PICALM expression correlates with AD pathology and cognitive decline.
- Amyloid-beta (Aβ) accumulation is a hallmark of AD, impacting brain homeostasis.
Purpose of the Study:
- To investigate the role of PICALM in regulating Aβ clearance across the blood-brain barrier (BBB).
- To elucidate the molecular mechanisms by which PICALM mediates Aβ transcytosis.
- To explore the therapeutic potential of PICALM in AD.
Main Methods:
- Studied PICALM expression in AD and murine brain endothelium.
- Assessed Aβ clearance across the murine BBB in Picalm-deficient models.
- Utilized human brain endothelial monolayers and induced pluripotent stem cell-derived endothelial cells.
- Investigated Aβ internalization and trafficking pathways involving PICALM, clathrin, and LRP1.
- Employed adenoviral-mediated PICALM transfer and analyzed genetic variants (rs3851179).
Main Results:
- Reduced PICALM expression in AD brains and endothelium correlated with Aβ pathology and cognitive impairment.
- Picalm deficiency impaired Aβ clearance across the murine BBB, exacerbating Aβ pathology.
- Endothelial PICALM re-expression reversed Aβ pathology in vivo.
- PICALM regulates Aβ internalization via clathrin-dependent pathways, binding to LRP1, and facilitates transcytosis through Rab5 and Rab11.
- AD-derived endothelial cells showed reduced PICALM levels and Aβ clearance, which was restored by PICALM transfer.
- Endothelial cells with the protective rs3851179 allele exhibited higher PICALM levels and enhanced Aβ clearance.
Conclusions:
- PICALM is a critical regulator of Aβ transcytosis and clearance across the BBB.
- Dysfunctional PICALM contributes to Aβ brain accumulation in AD.
- Modulating PICALM offers a promising therapeutic strategy for enhancing Aβ brain homeostasis and treating AD.
