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

• Published in: Scientific reports 2018-01, Vol.8 (1), p.1144-9, Article 1144
• Main Authors: Zhang, Can, Griciuc, Ana, Hudry, Eloise, Wan, Yu, Quinti, Luisa, Ward, Joseph, Forte, Angela M., Shen, Xunuo, Ran, ChongZhao, Elmaleh, David R., Tanzi, Rudolph E.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 14; 14/19; 631/378/1689/1283; 64/110; 64/60; 692/617/375/365/1283; 82/51; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Protein Precursor - antagonists & inhibitors; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Anti-Asthmatic Agents - pharmacology; Asthma; Beta protein; Brain - drug effects; Brain - metabolism; Brain - pathology; Cromolyn Sodium - pharmacology; Disease Models, Animal; Drug Combinations; Drug Repositioning; Gene Expression; Humanities and Social Sciences; Humans; Ibuprofen; Ibuprofen - pharmacology; Inflammation; Male; Mice; Mice, Transgenic; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; multidisciplinary; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neuroprotective Agents - pharmacology; Nonsteroidal anti-inflammatory drugs; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - biosynthesis; Phagocytosis; Phagocytosis - drug effects; Science; Science (multidisciplinary); Sodium; Transgenes; β-Amyloid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-19641-2

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 APP Swedish -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.