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Elmaleh, David

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Elmaleh

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Elmaleh, David

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2012 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.699710e5-ccb0-4887-933e-d1519252f90a

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    Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis
    (Nature Publishing Group UK, 2018) Zhang, Can; Griciuc, Ana; Hudry, Eloise; Wan, Yu; Quinti, Luisa; Ward, Joseph; Forte, Angela M.; Shen, Xunuo; Ran, Chongzhao; Elmaleh, David; Tanzi, Rudolph
    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.
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    Mannose-Binding Lectin Binds to Amyloid \(\beta\) Protein and Modulates Inflammation
    (Hindawi Publishing Corporation, 2012) Larvie, Mykol; Shoup, Timothy; Chang, Wei-Chuan; Chigweshe, Lorencia; Hartshorn, Kevan; White, Mitchell R.; Stahl, Gregory L.; Elmaleh, David; Takahashi, Kazue
    Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid \(\beta\) peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to A\(\beta\) are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.