WO2016201086A1 - Compositions et procédés pour stimuler la protéolyse non-amyloïdogénique à médiation adam10 de la protéine précurseur de l'amyloïde - Google Patents

Compositions et procédés pour stimuler la protéolyse non-amyloïdogénique à médiation adam10 de la protéine précurseur de l'amyloïde Download PDF

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Publication number
WO2016201086A1
WO2016201086A1 PCT/US2016/036666 US2016036666W WO2016201086A1 WO 2016201086 A1 WO2016201086 A1 WO 2016201086A1 US 2016036666 W US2016036666 W US 2016036666W WO 2016201086 A1 WO2016201086 A1 WO 2016201086A1
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WIPO (PCT)
Prior art keywords
ppara
adam10
neurons
agonist
mice
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PCT/US2016/036666
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English (en)
Inventor
Kalipada PAHAN
Grant T. CORBETT
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Rush University Medical Center
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Publication of WO2016201086A1 publication Critical patent/WO2016201086A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention generally relates to compositions and methods for stimulating ADAM10-mediated nonamyloidogenic proteolysis of amyloid precursor protein.
  • One aspect of the invention provides a method of preventing or treating Alzheimer's Disease including administrating a clinically effective amount of proliferator-activated receptor a ("PPARa”) or an agonist of PPARa to a human or veterinary subject in need of such treatment.
  • PPARa proliferator-activated receptor a
  • the agonist is an amphipathic carboxylic acid.
  • the agonist may be, for example, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate or fenofibrate.
  • Figure 1 PPARa deficiency results in impaired ADAM 10 expression.
  • A-D Quantitative PCR results of AdamW (A), Adam17 (B), Bacel (C), and Psenl (D) mRNA expression in the hippocampus and cortex of 4 month old wild-type (WT) Ppara ' ' and Pparb ' ' animals or in WT neurons knocked down for PPARy (PpargKD). Values are corrected for Gapdh and are expressed as percentage of WT.
  • E Subcellular and detergent-soluble (1 % CHAPS)
  • PPARa is constitutively expressed in the hippocampus and hippocampal neurons (11). Activation of PPARa induces the expression of ADAM10 and subsequent a-secretase proteolysis of APP. Furthermore, 5XFAD mice null for PPARa (5X/a-/-) exhibited exacerbated brain ⁇ load relative to traditional 5XFAD mice. These results highlight the importance of PPARa in reducing endogenous ⁇ production by shifting APP processing toward the a- secretase pathway.
  • Soluble APPa (sAPPa) and ⁇ were immunoprecipitated using the murine-specific antibody M3.2. Coprecipitates were resolved on 10-20% tris-tricine gels in a discontinuous tricine buffer system and transferred to nitrocellulose membranes in Towbin Buffer under semi-dry conditions (12V for 20 min). Membranes were boiled in PBS for 5 min prior to blocking and antibodies M3.2 or D54D2 were used to detect immunoprecipitated APP species. Soluble ⁇ ( ⁇ ) was precipitated from M3.2 immunodepleted media using antibody 22C11 and detected with an antibody specific to a ⁇ -secretase-cleaved APP neoepitope (Poly8134). ⁇ - secretase-cleaved APP C-terminal fragments ( ⁇ ) were first
  • A10CTF truncated, transmembrane C-terminal ADAM10 fragment
  • Example 6 Ablation of PPARa Propagates Cerebral ⁇ Load and Augments Lethality in 5XFAD mice.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne généralement des compositions et des procédés permettant de stimuler la protéolyse non-amyloïdogénique à médiation ADAMI O de la protéine précurseur de l'amyloïde. Un aspect de la présente invention concerne un procédé de prévention ou de traitement de la maladie d'Alzheimer consistant à administrer une quantité cliniquement efficace de récepteur alpha activé par les proliférateurs de peroxisomes (« PPARα ») ou un agoniste de PPARα à un sujet humain ou vétérinaire nécessitant un tel traitement.
PCT/US2016/036666 2015-06-12 2016-06-09 Compositions et procédés pour stimuler la protéolyse non-amyloïdogénique à médiation adam10 de la protéine précurseur de l'amyloïde WO2016201086A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562174867P 2015-06-12 2015-06-12
US62/174,867 2015-06-12

Publications (1)

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WO2016201086A1 true WO2016201086A1 (fr) 2016-12-15

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PCT/US2016/036666 WO2016201086A1 (fr) 2015-06-12 2016-06-09 Compositions et procédés pour stimuler la protéolyse non-amyloïdogénique à médiation adam10 de la protéine précurseur de l'amyloïde

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018126000A1 (fr) * 2016-12-29 2018-07-05 Rush University Medical Center Amélioration de l'activité locomotrice et augmentation de la longévité de sujets atteints de la céroïde-lipofuscinose neuronale infantile tardive par le gemfibrosil
EP3429671A4 (fr) * 2016-03-15 2019-10-16 Rush University Medical Center Composition et procédés pour stimulation de clairance de protéine bêta-amyloïde
WO2020082941A1 (fr) * 2018-10-24 2020-04-30 中国科学院昆明动物研究所 Utilisation du gemfibrosil et d'un dérivé de celui-ci pour le traitement et/ou la prévention d'une maladie neurodégénérative

Citations (4)

* Cited by examiner, † Cited by third party
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US5179097A (en) * 1991-06-10 1993-01-12 Angres Isaac A Salts of non-steroidal anti-inflammatory carboxylic acids and anti-lipidemic carboxylic acids
US20020055529A1 (en) * 1998-12-02 2002-05-09 Bisgaier Charles Larry Method for treating alzheimer's disease
US20120058992A1 (en) * 2008-04-29 2012-03-08 Pharnext Therapeutic approaches for treating alzheimer disease and related disorders through a modulation of angiogenesis
US20130336928A1 (en) * 2012-06-18 2013-12-19 Healthpartners Research & Education Methods and pharmaceutical compositions for treatment of central nervous system disorders with therapeutic agent(s) in patients with concurrent non-cns condition(s) or disorders contraindicating systemic administration of the therapeutic agent(s)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5179097A (en) * 1991-06-10 1993-01-12 Angres Isaac A Salts of non-steroidal anti-inflammatory carboxylic acids and anti-lipidemic carboxylic acids
US20020055529A1 (en) * 1998-12-02 2002-05-09 Bisgaier Charles Larry Method for treating alzheimer's disease
US20120058992A1 (en) * 2008-04-29 2012-03-08 Pharnext Therapeutic approaches for treating alzheimer disease and related disorders through a modulation of angiogenesis
US20130336928A1 (en) * 2012-06-18 2013-12-19 Healthpartners Research & Education Methods and pharmaceutical compositions for treatment of central nervous system disorders with therapeutic agent(s) in patients with concurrent non-cns condition(s) or disorders contraindicating systemic administration of the therapeutic agent(s)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CORBETT ET AL.: "Activation of peroxisome proliferator-activated receptor a stimulates ADAM10-mediated proteolysis of APP", PROC NATL ACAD SCI USA, vol. 112, 15 June 2015 (2015-06-15), pages 8445 - 50, XP055333247 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3429671A4 (fr) * 2016-03-15 2019-10-16 Rush University Medical Center Composition et procédés pour stimulation de clairance de protéine bêta-amyloïde
US11135180B2 (en) 2016-03-15 2021-10-05 Rush University Medical Center Composition and methods for stimulating clearance of amyloid-beta protein
US11844767B2 (en) 2016-03-15 2023-12-19 Rush University Medical Center Composition and methods for stimulating clearance of amyloid-beta protein
WO2018126000A1 (fr) * 2016-12-29 2018-07-05 Rush University Medical Center Amélioration de l'activité locomotrice et augmentation de la longévité de sujets atteints de la céroïde-lipofuscinose neuronale infantile tardive par le gemfibrosil
CN110167545A (zh) * 2016-12-29 2019-08-23 拉什大学医学中心 吉非罗齐对晚期婴儿型神经元蜡样质脂褐质沉积症患者寿命的增加和自发活动的改善
JP2020504752A (ja) * 2016-12-29 2020-02-13 ラッシュ・ユニバーシティ・メディカル・センター ゲムフィブロジルによる遅発型小児性神経セロイドリポフスチン沈着症の対象の自発運動の改善および寿命の増加
CN115192713A (zh) * 2016-12-29 2022-10-18 拉什大学医学中心 吉非罗齐对晚期婴儿型神经元蜡样质脂褐质沉积症患者寿命的增加和自发活动的改善
WO2020082941A1 (fr) * 2018-10-24 2020-04-30 中国科学院昆明动物研究所 Utilisation du gemfibrosil et d'un dérivé de celui-ci pour le traitement et/ou la prévention d'une maladie neurodégénérative
CN111084768A (zh) * 2018-10-24 2020-05-01 中国科学院昆明动物研究所 吉非罗齐及其衍生物用于治疗和/或预防神经退行性疾病的用途
US12048680B2 (en) 2018-10-24 2024-07-30 Kunming Institute Of Zoology Chinese Academy Of Sciences Use of Gemfibrozil and derivative thereof for treatment and/or prevention of neurodegenerative disease

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