WO2014053692A1 - Modèle animal de déficit cognitif, procédé d'obtention et applications - Google Patents

Modèle animal de déficit cognitif, procédé d'obtention et applications Download PDF

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WO2014053692A1
WO2014053692A1 PCT/ES2013/070693 ES2013070693W WO2014053692A1 WO 2014053692 A1 WO2014053692 A1 WO 2014053692A1 ES 2013070693 W ES2013070693 W ES 2013070693W WO 2014053692 A1 WO2014053692 A1 WO 2014053692A1
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megalin
mice
animal model
animal
model
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PCT/ES2013/070693
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Spanish (es)
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Eva María CARRO DÍAZ
Desiree Antequera Tienda
Consuelo PASCUAL PÉREZ
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Fundación Para La Investigación Biomédica Del Hospital 12 De Octubre
Centro De Investigación Biomédica En Red De Enfermedades Neurodegenerativas (Ciberned)
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Publication of WO2014053692A1 publication Critical patent/WO2014053692A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0276—Knock-out vertebrates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/20—Animal model comprising regulated expression system
    • A01K2217/206—Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0312—Animal model for Alzheimer's disease

Definitions

  • the present invention falls within the field of biotechnology. Specifically it refers to the development of nonhuman animals useful as models of human diseases related to cognitive deficits, and more specifically as a model of Alzheimer's.
  • Alzheimer's disease is one of the most important diseases in biomedical research. It is one of the neurodegenerative diseases that has the most impact on society. This disease causes a cognitive deterioration of the patient, and can end up developing in such a way that it can lead to the death of the patient. Due to the progressive aging of the population in industrialized countries, the mortality rate due to this disease is rising. The existence of a low number of useful drugs has led to a great development of the number of investigations carried out in order to know the pathogenesis of the disease. In addition, the number of compounds tested has been increased with the intention of finding treatments for the disease. However, at present it is still necessary to investigate in greater depth the pathophysiological mechanisms that the disease entails, and the search for drugs that allow a remission of the disease and an improvement in the quality of life of patients.
  • megalin / LRP2 a member of the family of low-density lipoprotein (LDL) receptor genes, is involved in the cellular uptake of various macromolecules, including numerous neurotrophic factors vital to the normal functioning of the brain.
  • Megalin also known as LRP-2 and glycoprotein 330, is the largest member of the low density lipoprotein receptor (LDLR) family, which also includes VLDLR, ApoER2 / LRP8, LRP1, LRP1 B, SorLA / LR1 1, LRP5, LRP6 and MEGF7 (Jaeger and Pietrzik, 2008, Curr Alzheimer Res 5 (1): 15-25; May et al., 2007, Ann Med 39 (3): 219-28).
  • LDLR low density lipoprotein receptor
  • Megalin is expressed in several absorbent epithelia, including renal proximal tubules, visceral vitelline vesicle, intestinal brush border, thyroid follicular cells, epididymis, male and female reproductive tracts and inner ear epithelium (Christensen and Birn, 2002, Nat Rev Mol Cell B ⁇ ol 3 (4): 256-66; Argraves and Morales, 2004, Mol Reprod Dev 69 (4): 419-27; Moestrupt and Verroust, 2001, Annu Rev Nutr 21: 407-28; Van Praet, 2003, Mol Reprod Dev 64 (2): 129-35).
  • megalin has been described in astrocytes (Bento-Abreu et al, 2008, J Neurochem 106 (3): 1 149-59), culture of granular neurons in the cerebellum (Ambj0rn et al, 2008, J Neurochem 104 (1 ): 21-37), sensory neurons (Fleming et al, 2009, J Neurosci. 29 (10): 3220-32) and cortical neurons (Chung et al, 2008, J Biol Chem. 283 (22): 15349-58 ; Alvira-Botero et al., 2010, Mol Cell Neurosci. 45 (3): 306-15).
  • megalin deficient animals revealed serious abnormalities in the development of the kidneys, lungs and CNS, consistent with the pattern of protein expression.
  • This phenotype is consistent with the role of megalin as an endocytic receptor that mediates the cellular uptake of essential nutrients, possibly derived from cholesterol lipoproteins, from the amniotic fluid in the rapid division of the neuroepithelium before the establishment of a complete circulatory system in the embryo ( Willnow et al, 1996, Proc Nati Acad Sci US A. 93 (16): 8460-4).
  • the present invention faces the need to find animal models of neurodegenerative diseases that allow the etiopathogenic study of these diseases, as well as the need for models that allow the analysis of drugs for the prevention and / or treatment of human disease.
  • the inventors demonstrate that by eliminating the expression of megalin (LRP-2) specifically in the endothelium of the cerebral capillaries of non-human animals, an animal model that presents cognitive deficit is obtained, and that reproduces behaviors similar to human diseases that present with cognitive deficit such as Alzheimer's.
  • LRP-2 megalin
  • a specific endothelial cell promoter and since the megalin in the endothelium is expressed exclusively in the cerebral capillaries, it is possible to eliminate the presence of megalin specifically in these cerebral capillaries, while It is still present in the other tissues that express it regularly.
  • the model thus generated presents behavioral alterations similar to those of other previously described models such as those of amyloidosis models.
  • the elimination of megalin must be carried out exclusively in the endothelium of the cerebral capillaries since otherwise, since megalin is a receptor present in various tissues, other defects would occur in the animal generated so that it would not present the same utility as in the present invention.
  • the absence of megalin in all tissues can cause that the correct development of these tissues or of the animal does not occur, which can cause premature death thereof due to developmental defects and therefore it is not possible for example the use of adult animals or studies that need long waiting times, such as the analysis of drug effects.
  • the deficiencies in the development of these tissues cause animals with absence of megalin in tissues other than vascular capillaries to present different utilities to the model of the present invention.
  • the model of the invention the animal can reach adulthood, and therefore it is useful for behavioral studies or for the identification and / or evaluation of compounds or compositions for the prevention or treatment of diseases related to a cognitive deficit .
  • a first aspect of the invention relates to a non-human animal model, hereinafter animal model of the invention, characterized by the absence of megalin located specifically in the endothelium of the cerebral capillaries.
  • the model of the invention is more useful when the model is a non-human mammal since it has characteristics more similar to those of human disease than in other types of animals. Therefore in one preferred embodiment of the first aspect of the invention the non-human animal is a non-human mammal.
  • the non-human mammal is a rodent or a primate. In an even more preferred embodiment of this aspect of the invention, the non-human mammal is a mouse.
  • the model of the invention can have any genetic background, although it is advantageous for said animal to be a normal animal that has no diagnosed pathologies.
  • abnormal applied to animals, as used in the present invention, refers to animals that lack transgenes or genetic alterations that could be involved in the pathogenesis of neurodegenerative diseases.
  • removal can be carried out by a transgenesis process in a way that does not allow the expression of the LRP-2 (low density lipoprotein receptor-related protein 2) or megalin gene in the cerebral capillaries.
  • This process can be carried out, for example, but not limited, as illustrated in the examples of the present invention, by the Cre / lox system under a specific tissue promoter, in this case endothelial cells such as the Tie-promoter. 2.
  • the Cre / lox system under a specific tissue promoter, in this case endothelial cells such as the Tie-promoter. 2.
  • the animals thus generated will present absence of megalin in the cerebral capillaries, maintaining the expression of this protein in the rest of tissues in which it is expressed in a normal animal such as, for example, choroidal plexus epithelial cells, neurons , astrocytes, epithelial cells of proximal tubules of the kidney, vitelline visceral sac, intestinal brush border, thyroid follicular cells, epididymis, reproductive tract and / or epithelium of the inner ear. Therefore, in another preferred embodiment of this aspect of the invention, the non-human animal is a transgenic animal.
  • a preferred embodiment of the first aspect of the invention relates to a nonhuman animal model of cognitive deficit characterized by the absence of megalin located specifically in the endothelium of the cerebral capillaries useful as an experimental model of a neurodegenerative disease.
  • a more preferred embodiment refers to a nonhuman animal model of cognitive deficit characterized by the absence of megalin located specifically in the endothelium of the cerebral capillaries useful as an experimental model of a neurodegenerative disease, where the neurodegenerative disease is Alzheimer's.
  • Another aspect of the invention relates to a process for obtaining the animal model of the invention, hereafter referred to as the method of invention, which comprises the elimination of megalin specifically in the endothelium of the cerebral capillaries.
  • the elimination of megalin can occur for example, but without being limited by transgenesis so that there is an inhibition of the expression of megalin in the endothelium of the cerebral capillaries specifically, without affecting cells of other tissues where it also occurs gene expression In this way the animal model of the invention can be obtained. Therefore, in a preferred embodiment of the method of the invention, the elimination of megalin is produced by transgenesis.
  • transgenesis refers to any technique or procedure that allows the integration into a series of cells of a living organism of an exogenous gene, or "transgene”, without affecting all of the cells of said organism, and which confers said cells and the organism that carries them a new biological property.
  • Said transgene or exogenous gene refers to a DNA that is not normally resident, nor present in the cell to be transformed.
  • the model of the invention can be obtained by different transgenesis strategies known to the expert. However, it is desirable that the process can be a controlled process to allow a better achievement of the model as well as a better use of the animal. Thus, as demonstrated in the examples of the invention, one of the possible strategies to be used is the use of the "Cre / lox" system controlled by a specific tissue promoter.
  • the model of the invention can be obtained by crossing animals that have substituted the endogenous Megalin sequence by the Megalin sequence flanked by the lox sequences, with animals having the Cre bacterial recombinase directed by a specific endothelial tissue promoter such as the Tie-2 promoter.
  • Cre recombinase is expressed in the endothelial tissue, and therefore only the capillaries Cerebral that is where megalin is expressed, will present absence of protein expression while in the rest of tissues this expression will not be affected. Therefore, in a more preferred embodiment of the method of the invention, the elimination of megalin is produced by transgenesis by the Cre / lox system. In an even more preferred embodiment, the Cre / lox system is controlled by the Tie2 promoter.
  • the model of the invention reproduces the behaviors that occur in diseases in which there is a cognitive deficit associated with dementia. Due to this, this model is useful for the study of diseases that present with cognitive deficit, such as, but not limited to, different neurodegenerative diseases such as Alzheimer's, vascular dementia, mild cognitive impairment or Parkinson's. Therefore, another aspect of the invention relates to the use of the model of the invention for the study of a neurodegenerative disease.
  • the neurodegenerative disease is a human neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • the model is also useful for the identification of compounds useful for the treatment of these diseases.
  • This animal model when developing common symptoms with these diseases, would be useful to test new drugs, the evolution of pharmacological treatments, their side effects, and all those aspects related to preclinical trials. Therefore, another aspect of the invention relates to the use of the model of the invention for the identification and evaluation of therapeutic compounds against a neurodegenerative disease.
  • the neurodegenerative disease is a human neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • Fig. 1 Shows the expression of megalin in EMD mice (Endothelial Megalin Deficient, or megalin deficient in brain capillaries), Wild-Type mice and in different tissues.
  • A) Immunohistochemistry shows megalin expression in endothelial cells in the brains of Wild-Type (WT) mice, and absence in EMD mice. The arrows indicate the expression of megalin.
  • C) Megalin expression is preserved in the choroidal plexus epithelial cells, both in wild (control) mice, and in EMD mice.
  • EMD megalin deficient mice in the cerebral capillaries; Wt: normal mice;
  • APP APP695 transgenic mice model of amyloidosis;
  • APP / Ps1 APP695 and Ps1 transgenic double mice, amyloidosis model.
  • the Cre / lox recombination system (Sauer & Henderson, 1988, Proc. Nati. Acad. Sci. USA 85,5166-5170; Sauer, 1993, Methods Enzymol. 225, has been used to carry out the model of the invention. 890-900) to eliminate the megalin gene exclusively in the cerebral capillaries.
  • the technique in this case consisted of the crossing of animals with transgenic Lox-Megalin sequences that replace the endogenous Megalin sequence, with animals that have the Cre bacterial recombinase directed by a tissue-specific promoter, in this case Tie2, specific of capillary endothelium.
  • Tie2-Cre transgenic mice mice presenting the cre gene encoding the Cre recombinase under the control of the Tie-2 promoter
  • megalin / gp330 megalin lox / lox
  • Tie2-Cre / megalin lox / lox mice were generated, which were called EMD ⁇ Endothelial Megalin Deficient, or megalin deficient in the cerebral capillaries) mice that present no expression of megalin expression in the endothelium of the cerebral capillaries.
  • Lox + / + mice which do not express Cre recombinase) bait brothers were used as controls.
  • BMECs cerebral microvasculature
  • the resulting homogenate was digested with collagenase (1 mg / mL) and DNAse (30 U / mL) in DMEM medium (containing 100 units / mL penicillin, 100 g / mL streptomycin, 50 g / mL gentamicin and 2 mM GlutaMAX-1) at 37 ° C for 40 minutes.
  • microvessel-rich precipitate was resuspended in DMEM and the mixture was seeded in culture plates previously coated with a coating buffer composed of fibronectin (0.05 mg / mL), collagen I (0.05 mg / mL) and collagen IV (0.1 mg / mL).
  • the seeded cells are incubated at 37 ° C for 24 hours in a humid environment (5% C02 / 95% air) in a 1: 1 DMEM mixture and an F12 nutrient mixture (DMEM / F-12) that has been supplemented with 20% of bovine plasma derivatives, penicillin (100 U / mL), streptomycin (100 g / mL), gentamicin (50 Mg / mL) and basic fibroblast growth factor (bFGF, 1 ng / mL).
  • DMEM / F-12 F12 nutrient mixture
  • bovine plasma derivatives penicillin (100 U / mL), streptomycin (100 g / mL), gentamicin (50 Mg / mL) and basic fibroblast growth factor (bFGF, 1 ng / mL).
  • bFGF basic fibroblast growth factor
  • BMVEC mouse cerebral capillary endothelial cells
  • Behavioral tests were performed at 6 months of age. After adaptation to human manipulation, behavioral tests were performed for 11 days.
  • the evaluation was completed by the object recognition test (days 10 and 1 1).
  • the open field was made in a maze with an area of 50 cm x 50 cm, walls 38 cm high and a central area with an area of 25 cm x 25 cm.
  • the mice were placed in a corner of the open field and evaluated in 5 min sessions for 3 days.
  • the entrances and the time elapsed in the central zone were determined as measures of behavior related to anxiety.
  • the recognition index defined as the ratio between the time spent exploring the new object and the scanning time of both objects, is used to measure memory.
  • mice A total of 62 male mice (27 EMD and 35 controls) were used in the study.
  • the behavior of two lines of transgenic mice models of amyloidosis was studied, transgenic mice that overexpress the human APP695 peptide, and double transgenic mice APP / Ps1, a cross between mice that overexpress the human APP695 peptide and the Mutant form Ps1 (M146L).
  • the behavior of the EMD mice and controls of 6 months of age was evaluated.
  • T-labyrinth test a significant increase in latency was found with respect to control mice that was similar to that shown by amyloidosis models, APP / PS1 mice and APP mice (Figure 2A).

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Abstract

L'invention concerne un modèle animal de déficit cognitif, lequel présente une absence de mégaline spécifiquement au niveau de l'endothélium des capillaires cérébraux, ainsi que son procédé d'obtention et son utilisation comme modèle de maladies neurodégénératives, plus concrètement dans l'Alzheimer.
PCT/ES2013/070693 2012-10-05 2013-10-07 Modèle animal de déficit cognitif, procédé d'obtention et applications WO2014053692A1 (fr)

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ESP201231533 2012-10-05

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059242A1 (fr) * 2005-11-15 2007-05-24 The University Of Rochester Elimination du peptide beta-amyloide par la proteine associee au recepteur des lipoproteines de basse densite 2 a travers la barriere hemato-encephalique par l'intermediaire de l'apolipoproteine j

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059242A1 (fr) * 2005-11-15 2007-05-24 The University Of Rochester Elimination du peptide beta-amyloide par la proteine associee au recepteur des lipoproteines de basse densite 2 a travers la barriere hemato-encephalique par l'intermediaire de l'apolipoproteine j

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BELL ROBERT D ET AL.: "Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system", JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM : OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF CEREBRAL BLOOD FLOW AND METABOLISM (2007), vol. 27, no. 5, 30 April 2007 (2007-04-30), pages 909 - 918 *
HAMMAD S M ET AL.: "Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide..", THE JOURNAL OF BIOLOGICAL CHEMISTRY (997), vol. 272, no. 30, 25 July 1997 (1997-07-25), pages 18644 - 18649 *
HATCH E ET AL.: "Transgenic mouse models of A beta transport in Alzheimer's disease", 40TH ANNUAL MEETING OF THE SOCIETY-FOR-NEUROSCIENCE, vol. 40, 13 November 2010 (2010-11-13), SAN DIEGO, CA, USA *
OLIVEIRA ET AL.: "Genetic reduction of megalin increases brain Abeta plaque burden: Evidence from a new mouse model of Alzheimer's disease", 41ST ANNUAL MEETING OF THE SOCIETY-FOR-NEUROSCIENCE, vol. 41, 12 November 2011 (2011-11-12), WASHINGTON, DC, USA *
WILLNOW T ET AL.: "Defective forebrain development in mice lacking gp330/megalin", PROC. NATL. ACAD. SCI., vol. 93, 1996, pages 8460 - 8464 *
ZLOKOVIC B ET AL.: "Glycoprotein 330/megalin: Probable role in receptor-mediatedtransport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid 13 at the blood-brain and blood-cerebrospinal fluid barriers", PROC. NATL. ACAD. SCI., vol. 93, 1996, pages 4229 - 4234 *

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