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Amyloid-? peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.

ABSTRACT: Passive immunization with anti-amyloid-? peptide (A?) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of A?-specific DARPins. We further showed their ability to delay A? aggregation and prevent A?-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent A?-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble A? levels. These findings demonstrate the therapeutic potential of A?-specific DARPins for the treatment of Alzheimer disease.

SUBMITTER: Hanenberg M

PROVIDER: S-EPMC4175345 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Amyloid-β peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.

Hanenberg Michael M McAfoose Jordan J Kulic Luka L Welt Tobias T Wirth Fabian F Parizek Petra P Strobel Lisa L Cattepoel Susann S Späni Claudia C Derungs Rebecca R Maier Marcel M Plückthun Andreas A Nitsch Roger M RM

The Journal of biological chemistry 20140812 39

Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profil ...[more]

PMID: 25118284

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Project description:Rationale: The accumulation and clearance of amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). The (re)discovery of meningeal lymphatic vessels in recent years has focused attention on the lymphatic clearance of Aβ and has become a promising therapeutic target for such diseases. However, there is a lack of small molecular compounds that could clearly regulate meningeal lymphatic drainage to remove Aβ from the brain. Methods: We investigated the effect of borneol on meningeal lymphatic clearance of macromolecules with different molecular weights (including Aβ) in the brain. To further investigate the mechanism of borneol regulating meningeal lymphatic drainage, immunofluorescence staining, western blotting, ELISA, RT-qPCR, and Nitric Oxide assay kits were used. The cognitive function of AD mice after borneol treatment was evaluated using two behavioral tests: open field (OF) and Morris water maze (MWM). Results: This study discovered that borneol could accelerate the lymphatic clearance of Aβ from the brain by enhancing meningeal lymphatic drainage. Preliminary mechanism analysis revealed that borneol could improve the permeability and inner diameter of lymphatic vessels, allowing macromolecules to drain into the cervical lymph nodes (CLNS) and then be transported to the lymphatic circulation. To speed up the clearance of macromolecules, borneol also stimulated lymphatic constriction by lowering the level of nitric oxide in the meninges. In addition, borneol stimulated lymphangiogenesis by increasing the levels of FOXC2, VEGFC, and LYVE-1 in the meninges, which promoted the clearance rates of macromolecules. Borneol improved meningeal lymphatic clearance not only for Aβ but also for other macromolecular polymers (molecular weight in the range of 2 KD - 45 KD. Borneol ameliorated cognitive deficits and alleviated brain Aβ burden in Aβ-injected mice. Conclusions: Our findings not only provide a strategy to regulate lymphatic clearance pathways of macromolecules in the brain, but also new targets and ideas for treating neurodegenerative diseases like AD. Furthermore, our findings indicate that borneol is a promising therapeutic drug for AD.

Dataset Information

Amyloid-? peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.

Publications

Amyloid-β peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.

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