Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance

Nat Neurosci. 2015 Jul;18(7):978-87. doi: 10.1038/nn.4025.

Zhen Zhao ¹, Abhay P Sagare ¹, Qingyi Ma ¹, Matthew R Halliday ¹, Pan Kong ¹, Kassandra Kisler ¹, Ethan A Winkler ², Anita Ramanathan ¹, Takahisa Kanekiyo ³, Guojun Bu ³, Nelly Chuqui Owens ¹, Sanket V Rege ¹, Gabriel Si ¹, Ashim Ahuja ¹, Donghui Zhu ⁴, Carol A Miller ⁵, Julie A Schneider ⁶, Manami Maeda ⁷, Takahiro Maeda ⁷, Tohru Sugawara ⁸, Justin K Ichida ⁸, Berislav V Zlokovic ¹

Affiliations

1 Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
2 1] Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. [2] Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
3 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
4 Department of Chemical, Biological and Bioengineering, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, USA.
5 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
6 Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
7 1] Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, California, USA. [2] Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
8 Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California, USA.

PMID: 26005850 DOI: 10.1038/nn.4025

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.

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