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A Food and Drug Administration-approved Asthma Therapeutic Agent Impacts Amyloid β in the Brain in a Transgenic Model of Alzheimer Disease*

Open AccessPublished:December 02, 2014DOI:https://doi.org/10.1074/jbc.M114.586602
      Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance from the brain are targets of anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food and Drug Administration-approved drug already in use for the treatment of asthma, efficiently inhibits the aggregation of Aβ monomers into higher-order oligomers and fibrils in vitro without affecting Aβ production. In vivo, the levels of soluble Aβ are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium. Additional in vivo microdialysis studies also show that this compound decreases the half-life of soluble Aβ in the brain. These data suggest a clear effect of a peripherally administered, Food and Drug Administration-approved medication on Aβ economy, supporting further investigation of the potential long-term efficacy of cromolyn sodium in Alzheimer disease.Cromolyn sodium is an FDA-approved drug structurally similar to fisetin, an antiamyloidogenic molecule.

      Results

      Cromolyn sodium interferes with amyloid β (Aβ) aggregation in vitro while rapidly decreasing the levels of soluble Aβ peptides in vivo after a week.

      Conclusion

      Cromolyn sodium may have an impact on amyloid economy.

      Significance

      Developing new disease-modifying therapeutics remains an urgent need in the treatment of Alzheimer disease.

      Introduction

      Therapies to prevent Alzheimer disease (AD)
      The abbreviations used are: AD
      Alzheimer disease
      amyloid β
      APP
      amyloid precursor protein
      ISF
      interstitial fluid
      Gdn-HCl
      guanidine-hydrogen chloride.
      progression remain a highly unmet medical need. Food and Drug Administration-approved drugs such as acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are indicated for symptomatic relief in patients with mild to moderate AD (
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      ). However, none of the molecules currently available efficiently target the underlying causative pathophysiological processes of the disease. The development of successful disease-modifying treatments, in contrast, would have a long-term beneficial outcome on the course of AD progression.
      The advent and spread of neurotoxic oligomeric aggregates of amyloid β (Aβ) is widely regarded as a key trigger in AD pathogenesis (
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      Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid β-protein.
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      ) cause AD, whereas a recently reported APP mutation has been shown to decrease Aβ by ∼40% and to be protective (
      • Jonsson T.
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      • Steinberg S.
      • Snaedal J.
      • Jonsson P.V.
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      • Stefansson H.
      • Sulem P.
      • Gudbjartsson D.
      • Maloney J.
      • Hoyte K.
      • Gustafson A.
      • Liu Y.
      • Lu Y.
      • Bhangale T.
      • Graham R.R.
      • Huttenlocher J.
      • Bjornsdottir G.
      • Andreassen O.A.
      • Jönsson E.G.
      • Palotie A.
      • Behrens T.W.
      • Magnusson O.T.
      • Kong A.
      • Thorsteinsdottir U.
      • Watts R.J.
      • Stefansson K.
      A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
      ,
      • Di Fede G.
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      • Levy E.
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      A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.
      ). Aberrant accumulation of Aβ peptides, rather than increased production, is believed to initiate the development of the sporadic form of the disease, which represents the vast majority of cases (
      • Ertekin-Taner N.
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      • Hutton M.
      • Younkin S.G.
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      ,
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      ,
      • Mawuenyega K.G.
      • Sigurdson W.
      • Ovod V.
      • Munsell L.
      • Kasten T.
      • Morris J.C.
      • Yarasheski K.E.
      • Bateman R.J.
      Decreased clearance of CNS β-amyloid in Alzheimer's disease.
      ). Misfolded Aβ monomers can aggregate into higher-order oligomers, eventually forming fibrils that are deposited into the extracellular space to form fibrillar amyloid neuritic plaques. Aβ oligomers have a longer half-life in the interstitial fluid than monomers so that their formation influences Aβ levels (
      • Takeda S.
      • Hashimoto T.
      • Roe A.D.
      • Hori Y.
      • Spires-Jones T.L.
      • Hyman B.T.
      Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease.
      ). Aβ oligomers rather than monomers have been shown to be neurotoxic for neurons (
      • Townsend M.
      • Shankar G.M.
      • Mehta T.
      • Walsh D.M.
      • Selkoe D.J.
      Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers.
      ), inhibiting long-term potentiation (LTP), leading to neuronal stress, abnormal tau phosphorylation, synapse collapse, and memory impairment (
      • Tomiyama T.
      • Matsuyama S.
      • Iso H.
      • Umeda T.
      • Takuma H.
      • Ohnishi K.
      • Ishibashi K.
      • Teraoka R.
      • Sakama N.
      • Yamashita T.
      • Nishitsuji K.
      • Ito K.
      • Shimada H.
      • Lambert M.P.
      • Klein W.L.
      • Mori H.
      A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal Tau phosphorylation, glial activation, and neuronal loss in vivo.
      ,
      • Koffie R.M.
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      • Hashimoto T.
      • Adams K.W.
      • Mielke M.L.
      • Garcia-Alloza M.
      • Micheva K.D.
      • Smith S.J.
      • Kim M.L.
      • Lee V.M.
      • Hyman B.T.
      • Spires-Jones T.L.
      Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques.
      ,
      • Shankar G.M.
      • Li S.
      • Mehta T.H.
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      • Farrell M.A.
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      • Selkoe D.J.
      Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
      ,
      • Lesné S.
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      • Kayed R.
      • Glabe C.G.
      • Yang A.
      • Gallagher M.
      • Ashe K.H.
      A specific amyloid-β protein assembly in the brain impairs memory.
      ,
      • Cleary J.P.
      • Walsh D.M.
      • Hofmeister J.J.
      • Shankar G.M.
      • Kuskowski M.A.
      • Selkoe D.J.
      • Ashe K.H.
      Natural oligomers of the amyloid-β protein specifically disrupt cognitive function.
      ,
      • Walsh D.M.
      • Klyubin I.
      • Fadeeva J.V.
      • Cullen W.K.
      • Anwyl R.
      • Wolfe M.S.
      • Rowan M.J.
      • Selkoe D.J.
      Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo.
      ). Therefore, therapeutic agents able to decrease Aβ levels, prevent oligomer formation, or disaggregate soluble oligomers may be of therapeutic interest.
      Cromolyn sodium is a Food and Drug Administration-approved drug used in the treatment of asthma. Because of its close structural homology with fisetin (3,3′,4′,7-tetrahydroxyflavone) (
      • Akaishi T.
      • Morimoto T.
      • Shibao M.
      • Watanabe S.
      • Sakai-Kato K.
      • Utsunomiya-Tate N.
      • Abe K.
      Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein.
      ), a neurotrophic molecule that has been shown previously to inhibit amyloid aggregation (
      • Ushikubo H.
      • Watanabe S.
      • Tanimoto Y.
      • Abe K.
      • Hiza A.
      • Ogawa T.
      • Asakawa T.
      • Kan T.
      • Akaishi T.
      3,3′,4′,5,5′-Pentahydroxyflavone is a potent inhibitor of amyloid β fibril formation.
      ), we hypothesized that cromolyn sodium may potentially prevent Aβ oligomerization and promote Aβ clearance in vitro and in vivo. In addition, the use of cromolyn sodium in addiction models (after subcutaneous infusion (
      • Leza J.C.
      • Lizasoain I.
      • San-Martín-Clark O.
      • Lorenzo P.
      Morphine-induced changes in cerebral and cerebellar nitric oxide synthase activity.
      ,
      • San-Martín-Clark O.
      • Cuéllar B.
      • De Alba J.
      • Leza J.C.
      • Lorenzo P.
      Changes induced by sodium cromoglycate in brain catecholamine turnover in morphine dependent and abstinent mice.
      )) and the physical properties of this molecule (molecular weight: 508.38; polar surface area: 125; and LogP: 1.39) argue for cromolyn sodium as a blood-brain barrier-permeable drug, therefore allowing systemic infusion. In this study, we tested the hypotheses that cromolyn sodium can alter Aβ aggregation after peripheral delivery. In this study, we demonstrated that cromolyn sodium efficiently prevents the aggregation of monomeric amyloid peptides into higher-order oligomers and fibrils in vitro. In addition, in vivo intraperitoneal administration of this compound rapidly decreases the amount of soluble monomeric Aβ in the brain by ∼50% after only 1 week of treatment and, more specifically, within the interstitial fluid that contains neurotoxic molecules directly in contact with the neuropil. Using in vivo microdialysis, we showed that the half-life of Aβ was significantly reduced in cromolyn sodium-treated mice compared with PBS-exposed animals, suggesting that preventing Aβ oligomerization may favor their clearance from the central nervous system. In addition, both in vivo and in vitro results suggest that Aβ uptake by microglial cells may be exacerbated in presence of cromolyn sodium. Overall, these results suggest that cromolyn sodium may be of interest in changing cerebral Aβ metabolism, with potential impact on toxic oligomers.

      DISCUSSION

      Amyloid-reducing agents remain potentially promising therapeutic drugs in the treatment of Alzheimer disease as the only molecules currently available that mainly target associated symptoms rather than the neuropathological causes of the disease. Cromolyn sodium is a synthetic chromone derivative that has been approved for use by the Food and Drug Administration since the 1970s for the treatment of asthma (
      • Cockcroft D.W.
      Pharmacologic therapy for asthma: overview and historical perspective.
      ,
      • Storms W.
      • Kaliner M.A.
      Cromolyn sodium: fitting an old friend into current asthma treatment.
      ). For asthma treatment, cromolyn sodium powder is micronized for inhalation to the lungs via dry powder inhaler, whereas liquid intranasal and ophthalmic formulations have also been developed for the treatment of rhinitis and conjunctivitis (
      • Ratner P.H.
      • Ehrlich P.M.
      • Fineman S.M.
      • Meltzer E.O.
      • Skoner D.P.
      Use of intranasal cromolyn sodium for allergic rhinitis.
      ). The broad use of cromolyn sodium in the treatment of several diseases, its capacity to cross the blood-brain barrier after peripheral injection in rodents (
      • Leza J.C.
      • Lizasoain I.
      • San-Martín-Clark O.
      • Lorenzo P.
      Morphine-induced changes in cerebral and cerebellar nitric oxide synthase activity.
      ,
      • San-Martín-Clark O.
      • Cuéllar B.
      • De Alba J.
      • Leza J.C.
      • Lorenzo P.
      Changes induced by sodium cromoglycate in brain catecholamine turnover in morphine dependent and abstinent mice.
      ), and its structural similarity with fisetin, an anti-amyloid compound that has been shown to inhibit amyloid fibril formation (
      • Akaishi T.
      • Morimoto T.
      • Shibao M.
      • Watanabe S.
      • Sakai-Kato K.
      • Utsunomiya-Tate N.
      • Abe K.
      Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein.
      ) and has neuroprotective functions in vitro and in vivo (
      • Maher P.
      • Akaishi T.
      • Abe K.
      Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory.
      ,
      • Ishige K.
      • Schubert D.
      • Sagara Y.
      Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms.
      ), raise the possibility that cromolyn sodium may also have a beneficial effect on Alzheimer disease.
      In this study, we demonstrated that addition of cromolyn sodium to Aβ40 and Aβ42 preparations not only prevents amyloid fibril formation but also inhibits Aβ oligomerization in vitro, therefore potentially preventing the formation of the most neurotoxic species of amyloid (
      • Townsend M.
      • Shankar G.M.
      • Mehta T.
      • Walsh D.M.
      • Selkoe D.J.
      Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers.
      ,
      • Tomiyama T.
      • Matsuyama S.
      • Iso H.
      • Umeda T.
      • Takuma H.
      • Ohnishi K.
      • Ishibashi K.
      • Teraoka R.
      • Sakama N.
      • Yamashita T.
      • Nishitsuji K.
      • Ito K.
      • Shimada H.
      • Lambert M.P.
      • Klein W.L.
      • Mori H.
      A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal Tau phosphorylation, glial activation, and neuronal loss in vivo.
      ,
      • Koffie R.M.
      • Meyer-Luehmann M.
      • Hashimoto T.
      • Adams K.W.
      • Mielke M.L.
      • Garcia-Alloza M.
      • Micheva K.D.
      • Smith S.J.
      • Kim M.L.
      • Lee V.M.
      • Hyman B.T.
      • Spires-Jones T.L.
      Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques.
      ,
      • Shankar G.M.
      • Li S.
      • Mehta T.H.
      • Garcia-Munoz A.
      • Shepardson N.E.
      • Smith I.
      • Brett F.M.
      • Farrell M.A.
      • Rowan M.J.
      • Lemere C.A.
      • Regan C.M.
      • Walsh D.M.
      • Sabatini B.L.
      • Selkoe D.J.
      Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
      ,
      • Lesné S.
      • Koh M.T.
      • Kotilinek L.
      • Kayed R.
      • Glabe C.G.
      • Yang A.
      • Gallagher M.
      • Ashe K.H.
      A specific amyloid-β protein assembly in the brain impairs memory.
      ,
      • Cleary J.P.
      • Walsh D.M.
      • Hofmeister J.J.
      • Shankar G.M.
      • Kuskowski M.A.
      • Selkoe D.J.
      • Ashe K.H.
      Natural oligomers of the amyloid-β protein specifically disrupt cognitive function.
      ,
      • Walsh D.M.
      • Klyubin I.
      • Fadeeva J.V.
      • Cullen W.K.
      • Anwyl R.
      • Wolfe M.S.
      • Rowan M.J.
      • Selkoe D.J.
      Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo.
      ). Importantly, short-term exposure with peripherally administered cromolyn sodium also efficiently impacts Aβ economy in vivo, an effect detectable after only 1 week of treatment. We observed that intraperitoneal administration of cromolyn sodium reduces the levels of TBS-, Triton X-, and SDS-soluble Aβ monomers in the brain within days in a dose-dependent fashion. However, the concentrations of oligomers and fibrillar amyloid remain unchanged during the same period of time. Microdialysis experiments also show that the half-life of Aβ is shorter in the presence of cromolyn sodium, leading to lower total amounts in the brain. Interestingly, these significant modifications detected in the central nervous system did not impact the plasma concentrations of Aβ but may rather be related to activation of microglial cells and an increased efficiency of microglial clearance of intracerebral Aβ peptides.
      The specific effect of cromolyn sodium on Aβ monomers versus oligomers (assessed with two different assays, the addition of guanidine hydrochloride to break apart oligomeric structures and the use of an established same-site ELISA assay that specifically differentiates monomeric from oligomeric species) may be surprising because we anticipated that the mobilization of one pool of amyloid would have induced a concomitant decrease in small soluble aggregates. However, oligomeric Aβ species have been shown previously to have a longer ISF half-life (
      • Takeda S.
      • Hashimoto T.
      • Roe A.D.
      • Hori Y.
      • Spires-Jones T.L.
      • Hyman B.T.
      Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease.
      ), therefore suggesting that a longer chronic exposure time to cromolyn sodium may be needed to detect a significant decrease in the levels of oligomers. It also explains why the overall impact of cromolyn sodium on Aβ42 is less compared with Aβ40, considering the higher potency of Aβ42 to aggregate. Our results illustrate the complex relationships between the kinetics of monomeric and oligomeric Aβ in the interstitial fluid in vivo. Nonetheless, the marked change in soluble monomeric Aβ levels after only a week of treatment with cromolyn sodium is remarkable, with about 50% reduction in the content of Aβ after a few days, an effect of the same order of magnitude as the decrease seen in patients who have inherited a protective mutation in APP (
      • Jonsson T.
      • Atwal J.K.
      • Steinberg S.
      • Snaedal J.
      • Jonsson P.V.
      • Bjornsson S.
      • Stefansson H.
      • Sulem P.
      • Gudbjartsson D.
      • Maloney J.
      • Hoyte K.
      • Gustafson A.
      • Liu Y.
      • Lu Y.
      • Bhangale T.
      • Graham R.R.
      • Huttenlocher J.
      • Bjornsdottir G.
      • Andreassen O.A.
      • Jönsson E.G.
      • Palotie A.
      • Behrens T.W.
      • Magnusson O.T.
      • Kong A.
      • Thorsteinsdottir U.
      • Watts R.J.
      • Stefansson K.
      A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
      ), suggesting that this magnitude of reduction in Aβ, if sustained chronically, may have important effects in AD.
      Finally, numerous synthetic or naturally occurring compounds (such as curcuminoids or flavonoids (
      • Kim H.
      • Park B.S.
      • Lee K.G.
      • Choi C.Y.
      • Jang S.S.
      • Kim Y.H.
      • Lee S.E.
      Effects of naturally occurring compounds on fibril formation and oxidative stress of β-amyloid.
      )), small peptides (eventually derived from Aβ itself (
      • Sciarretta K.L.
      • Gordon D.J.
      • Meredith S.C.
      Peptide-based inhibitors of amyloid assembly.
      )), endogenously expressed chaperones (such as DNAJB6 (
      • Månsson C.
      • Arosio P.
      • Hussein R.
      • Kampinga H.H.
      • Hashem R.M.
      • Boelens W.C.
      • Dobson C.M.
      • Knowles T.P.
      • Linse S.
      • Emanuelsson C.
      Interaction of the molecular chaperone DNAJB6 with growing amyloid-β 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation.
      )), or even synthetic nucleotides (
      • Abraham J.N.
      • Kedracki D.
      • Prado E.
      • Gourmel C.
      • Maroni P.
      • Nardin C.
      Effect of the interaction of the amyloid β (1-42) peptide with short single-stranded synthetic nucleotide sequences: morphological characterization of the inhibition of fibrils formation and fibrils disassembly.
      ) have been reported previously to prevent Aβ aggregation into higher-order species or fibrils. Despite their potency to inhibit or destabilize the formation of amyloid fibrils in vitro, so far only a few of these compounds have been associated with an impact on the neuropathological hallmarks of the disease in vivo. Among them, curcuminoids and flavoinoids have been associated with decreased Aβ deposition, Aβ-dependent neurotoxicity, and improved cognitive functions in AD mouse models, an effect reported after weeks or months of treatments (
      • Quitschke W.W.
      • Steinhauff N.
      • Rooney J.
      The effect of cyclodextrin-solubilized curcuminoids on amyloid plaques in Alzheimer transgenic mice: brain uptake and metabolism after intravenous and subcutaneous injection.
      ,
      • Currais A.
      • Prior M.
      • Dargusch R.
      • Armando A.
      • Ehren J.
      • Schubert D.
      • Quehenberger O.
      • Maher P.
      Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice.
      ,
      • Kim D.S.
      • Kim J.Y.
      • Han Y.
      Curcuminoids in neurodegenerative diseases.
      ). However, besides their evident inhibitory effect on Aβ aggregation in vitro, those particular compounds also modulate other processes (such as inflammation, oxidative stress, or endoplasmic reticulum stress) that concomitantly counteract the buildup of amyloid within the brain but also alleviate Aβ-related deleterious effects. It is also difficult to draw a clear conclusion regarding the potential therapeutic impact of cromolyn sodium compared with other antifibrillogenic molecules, considering that the duration of exposure, the route of administration (intravenous, intracerebroventricular infusion, intraperitoneal injection, etc.), and the cellular or animal models are highly variable between studies.
      In conclusion, additional investigations will be necessary to determine whether appropriate levels of cromolyn sodium can reach the central nervous system in patients, and further studies will be needed to understand the mechanisms of action of cromolyn sodium on Aβ fibrillization and clearance. In particular, the anti-inflammatory effect of this molecule has been well reported in the treatment of asthma, a property that may also contribute to its potential beneficial impact in AD.

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