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Sci Rep. 2018 Jan 18;8(1):1144. doi: 10.1038/s41598-018-19641-2.

Cromolyn Reduces Levels of the Alzheimer's Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis.

Author information

1
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA.
2
Alzheimer's Disease Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA.
3
Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA.
4
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA. tanzi@helix.mgh.harvard.edu.

Abstract

Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer's disease (AD). Aβ deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aβ levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APPSwedish-expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of β-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aβ species, i.e. Aβ40 and Aβ42, but increased insoluble Aβ38 levels. In addition to its anti-aggregation effects on Aβ, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of β-amyloid deposits in AD mice. Cromolyn also promoted Aβ42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aβ levels and inducing a neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.

PMID:
29348604
PMCID:
PMC5773545
DOI:
10.1038/s41598-018-19641-2
[Indexed for MEDLINE]
Free PMC Article

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