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Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance
Open accessAbstract
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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In the citing paper
“Similarly, several genes reported to be involved in Aβ catabolism, such as RAB5A, RAB11A, CLU, and LRP2 (49–53), were also down-regulated in AD monocytes, suggesting the impaired Aβ catabolism in AD monocytes.”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [51]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“PICALM is enriched in the endothelium of human cerebral vessels including capillaries, but is downregulated in AD patients (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“PICALM controls receptor internalization and subsequent intracellular trafficking (683), via R-SNARE-mediated fusion of clathrin-coated vesicles with endosomes (411).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“Specifically, LRP1 facilitates clathrin-dependent, receptor-mediated endothelial endocytosis of A 𝛃 at the abluminal membrane of the BBB, which requires phosphatidylinositol binding clathrin assembly protein (PICALM) (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“PICALM guides transendothelial trafficking of endocytotic A 𝛃 -containing vesicles to Rab5, and then to Rab11 small GTPase leading to exocytosis of A 𝛃 across the luminal membrane of the BBB into the blood (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“As shown in the Picalm + / -; APP Swe mice, diminished PICALM levels at the BBB accelerate amyloid pathology and behavioral deficits, which can be ameliorated by endothelial re-expression of Picalm using an adeno-associated virus (AAV) (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“Endothelial cells derived from human iPSCs carrying homozygous protective rs3851179 A alleles exhibited increased PICALM expression and improved transvascular clearance of A 𝛃 across human BBB in vitro, when compared with isogenic cells from iPSCs carrying homozygous risk rs3851179 G alleles (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“Although most of the PICALM single nucleotide variants (SNPs) associated with late-onset AD are located outside of the coding regions (683), the risk alleles of rs3851179 (236) and rs10792832 (344) lead to lower expression of PICALM isoform 2 in the frontal and temporal cortex in the human brain on the expression quantitative trait loci (eQTLs) (586), indicating that lower PICALM levels may”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
The cited source says what the claim attributes to it.
In the citing paper
“These functions are central to its role in the clearance of both tau through autophagy (423) and A 𝛃 via transvascular transport across the BBB (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [683]
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In the citing paper
“The brain-to-blood transfer of monomeric Aβ is highly dependent on low-density lipoprotein receptor-related protein 1 (LRP1) [13, 14], which in brain endothelium is primarily located at the abluminal side [13, 15].”
From PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier (2022) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“More recently, PICALM has been described in vitro and in vivo to participate to Aβ transcytosis and clearance at the BBB through clathrin-dependent internalisation of Aβ after its binding to the LDLR-related protein-1 [157].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [157]
In the citing paper
“For previously reported loci, applying the same prioritization approach highlights several genes, as described in Fig. 2, some of which are involved in APP metabolism (FERMT2, PICALM) or tau toxicity (BIN1, CD2AP, FERMT2, CASS4, PTK2B)98–101.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [101]
In the citing paper
“Several genes encoding proteins intimately associated with the endothelium and Aβ clearance are highly validated AD risk factors, such as APOEε4, PICALM, and CLU [50, 51].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [51]
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1 retracted
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Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
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Metadata
- Authors
- Zhao, Z., Sagare, A. P., Ma, Q., Halliday, M. R., Kong, P., Kisler, K., Winkler, E. A., Ramanathan, A., Kanekiyo, T., Bu, G., Owens, N. C., Rege, S. V., Si, G., Ahuja, A., Zhu, D., Miller, C. A., Schneider, J. A., Maeda, M., Maeda, T., Sugawara, T., Ichida, J. K., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- Mayo Clinic (US)
- North Carolina Agricultural and Technical State University (US)
- Rush University Medical Center (US)
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-05-25
- Volume
- 18
- Issue
- 7
- Pages
- 978-987
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4482781
- OpenAlex
- W1516940938
- Cited by
- 410
- References
- 59
- Citations by year
- 2026: 26 · 2025: 24 · 2024: 32 · 2023: 36 · 2022: 31 · 2021: 36 · 2020: 50 · 2019: 48 · 2018: 50 · 2017: 30 · 2016: 33 · 2015: 14
- FWCI
- 31.19
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-11-20)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- The Scholars Repository - LLU (Loma Linda University) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (P01AG030128, R01AG039452, R01AG027924, R37AG023084, P50AG005142, RF1AG046205, R37AG23084, R01AG046205, R01AG035355, P50AG016574)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R00-NS07743, R37NS34467, P01NS074969)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- PICALM, amyloid-beta, blood-brain barrier, transcytosis, amyloid-beta clearance, Alzheimer's disease, brain endothelium, clathrin-mediated endocytosis, LRP1, Rab5, Rab11, cognitive impairment, iPSC-derived endothelial cells, adenoviral gene transfer
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Capillaries, Cerebral Cortex, Endothelium, Vascular, Homeostasis, Humans, Metabolic Clearance Rate, Amyloid beta-Peptides, Mice, Knockout, Monomeric Clathrin Assembly Proteins, Pluripotent Stem Cells, Mice, Transcytosis
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