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

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-? (A?) pathology and cognitive impairment. Moreover, Picalm deficiency diminished A? clearance across the murine blood-brain barrier (BBB) and accelerated A? 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 A? bound to the low density lipoprotein receptor related protein-1, a key A? clearance receptor, and guided A? trafficking to Rab5 and Rab11, leading to A? endothelial transcytosis and clearance. PICALM levels and A? 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 A? clearance. Thus, PICALM regulates A? BBB transcytosis and clearance, which has implications for A? brain homeostasis and clearance therapy.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC4482781 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Zhao Zhen Z Sagare Abhay P AP Ma Qingyi Q Halliday Matthew R MR Kong Pan P Kisler Kassandra K Winkler Ethan A EA Ramanathan Anita A Kanekiyo Takahisa T Bu Guojun G Owens Nelly Chuqui NC Rege Sanket V SV Si Gabriel G Ahuja Ashim A Zhu Donghui D Miller Carol A CA Schneider Julie A JA Maeda Manami M Maeda Takahiro T Sugawara Tohru T Ichida Justin K JK Zlokovic Berislav V BV

Nature neuroscience 20150525 7

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/cl ...[more]

PMID: 26005850

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Project description:Alzheimer's disease (AD) has a characteristic hallmark of amyloid-? (A?) accumulation in the brain. This accumulation of A? has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate A? clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient A? clearance. However, the contribution of each process to A? clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect A? clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to A? clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-A?40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare A? clearance between mouse and human BBB models. Kinetic studies for A?40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-A?40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-A?40 and the rate of each process. Established mechanistic model suggested significantly higher rates of A? uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-A?40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of A? from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to A? clearance and offer, for the first time, a mathematical model that describes A? clearance across BBB.

Dataset Information

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

Publications

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

Similar Datasets

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