Dataset Information

Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.

ABSTRACT: Decreased clearance is the main reason amyloid-beta protein (Abeta) is increased in the brains of patients with Alzheimer's disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Abeta at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Abeta42, increased brain levels of Abeta42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Abeta could increase and AD would be promoted.

SUBMITTER: Jaeger LB

PROVIDER: S-EPMC2802833 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Publications

Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.

Jaeger Laura B LB Dohgu Shinya S Hwang Mark C MC Farr Susan A SA Murphy M Paul MP Fleegal-DeMotta Melissa A MA Lynch Jessica L JL Robinson Sandra M SM Niehoff Michael L ML Johnson Steven N SN Kumar Vijaya B VB Banks William A WA

Journal of Alzheimer's disease : JAD 20090101 3

Decreased clearance is the main reason amyloid-beta protein (Abeta) is increased in the brains of patients with Alzheimer's disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Abeta at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorot ...[more]

PMID: 19433890

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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

Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.

Publications

Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.

Similar Datasets

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