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Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease.

Abstract

The deposition of amyloid-β (Aβ) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aβ in production and clearance seems to be the reason for an enhanced Aβ accumulation. Besides a systematic clearance through the blood-brain barrier, Aβ is cleared from the brain by Aβ-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aβ-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP-/-), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/- mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aβ42 as well as region-specific increases in extracellular Aβ deposition. Surprisingly, in young mice, a more abundant cortical Aβ plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/- mice. Additionally, young 5XFAD/NEP+/- as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aβ peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/- mice and might suggest a reciprocal effect between ECE and NEP activities in Aβ degradation.

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  • Authors+Show Affiliations

    ,

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    ,

    Molecular Neuropathology Group, Department of Neuropathology, Heinrich-Heine-University, Duesseldorf, Germany.

    ,

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    ,

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    ,

    Molecular Neuropathology Group, Department of Neuropathology, Heinrich-Heine-University, Duesseldorf, Germany.

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    Source

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Analysis of Variance
    Animals
    Aspartic Acid Endopeptidases
    Brain
    Disease Models, Animal
    Endothelin-Converting Enzymes
    Gene Expression Regulation
    Glial Fibrillary Acidic Protein
    Humans
    Maze Learning
    Memory Disorders
    Metalloendopeptidases
    Mice
    Mice, Inbred C57BL
    Mice, Transgenic
    Neprilysin
    Presenilin-1
    RNA, Messenger

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25408216

    Citation

    Hüttenrauch, Melanie, et al. "Neprilysin Deficiency Alters the Neuropathological and Behavioral Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease." Journal of Alzheimer's Disease : JAD, vol. 44, no. 4, 2015, pp. 1291-302.
    Hüttenrauch M, Baches S, Gerth J, et al. Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease. J Alzheimers Dis. 2015;44(4):1291-302.
    Hüttenrauch, M., Baches, S., Gerth, J., Bayer, T. A., Weggen, S., & Wirths, O. (2015). Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease. Journal of Alzheimer's Disease : JAD, 44(4), pp. 1291-302. doi:10.3233/JAD-142463.
    Hüttenrauch M, et al. Neprilysin Deficiency Alters the Neuropathological and Behavioral Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2015;44(4):1291-302. PubMed PMID: 25408216.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease. AU - Hüttenrauch,Melanie, AU - Baches,Sandra, AU - Gerth,Janina, AU - Bayer,Thomas A, AU - Weggen,Sascha, AU - Wirths,Oliver, PY - 2014/11/20/entrez PY - 2014/11/20/pubmed PY - 2015/11/10/medline KW - Alzheimer's disease KW - AβPP KW - amyloid KW - endothelin-converting enzyme KW - intraneuronal Aβ KW - neprilysin KW - transgenic mice KW - working memory SP - 1291 EP - 302 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 44 IS - 4 N2 - The deposition of amyloid-β (Aβ) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aβ in production and clearance seems to be the reason for an enhanced Aβ accumulation. Besides a systematic clearance through the blood-brain barrier, Aβ is cleared from the brain by Aβ-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aβ-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP-/-), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/- mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aβ42 as well as region-specific increases in extracellular Aβ deposition. Surprisingly, in young mice, a more abundant cortical Aβ plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/- mice. Additionally, young 5XFAD/NEP+/- as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aβ peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/- mice and might suggest a reciprocal effect between ECE and NEP activities in Aβ degradation. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/25408216/Neprilysin_deficiency_alters_the_neuropathological_and_behavioral_phenotype_in_the_5XFAD_mouse_model_of_Alzheimer's_disease_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-142463 DB - PRIME DP - Unbound Medicine ER -