Functional role of meprin beta in Alzheimer s disease

• Applicants: Professor Dr. Christoph Becker-Pauly; Professor Dr. Claus Ulrich Pietrzik
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Biochemistry ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236873051

• Final Report Year: 2020

Final Report Abstract

Late-onset Alzheimer’s disease (AD), the most common neurodegenerative disorder, is a progressive and an incurable form of dementia that develops in the elderly population usually over 65 years of age. It has been estimated that in 2050 worldwide 106 million patients will suffer from this disease. In brains of AD patients, loss of neurons and synapses occur as a result of the accumulation of amyloid β (Aβ) peptides. The aspartyl protease BACE1 was identified as the major amyloid precursor protein (APP)- cleaving β-secretase. However, certain AD associated N-terminally truncated Aβ peptides could not be assigned to BACE1 activity, indicating the presence of additional β-secretases. We demonstrated that the metalloproteinase meprin β is capable of generating truncated Aβ2-x peptides that have been described in AD patients, which indicates an important and BACE-independent contribution of the metalloprotease meprin β within the amyloidogenic pathway. The major aim of this project, which was transferred into project A15 of the CRC877 and is still funded, was to investigate, if meprin β is capable of generating Aβ peptides in vivo. We could clearly demonstrate that this is the case, proven with the help of different genetically modified mice, either lacking meprin β or overexpressing the protease in brain tissue. Hence, meprin β is an alternative β-secretase and with regard to its increased expression in AD brain, it represents another potential pharmacological target for the treatment of AD. Since we have shown that the APP sequence harboring the APP Swedish mutation (APPswe) is not effectively targeted by meprin β we hypothesize that N-terminal truncated Aβ peptides derived by meprin β cannot be detected in most AD mouse models, since they do express APPswe. Hence we crossed meprin β knock-out mice to mice overexpressing APP with the london mutation hAPP[V717I]. Analysis of these mice revealed, that we do see a decrease in Aβ generation, reduced N-terminal truncated Aβ peptide deposition and a bifacial behavioral phenotype compared to hAPP[V717I] mice. Employing a different genetic strategy, we bred Mep1b knock-in mice with GFAP-Cre driver mice and thereby generated mice that overexpress meprin β specifically in astrocytes. We could successfully induce expression of meprin β in the brain, detected by immunoblotting using HA-tag or meprin β specific antibodies. Of note, the levels of sAPPβ and most importantly of Aβx-40 peptides were significantly increased in these mice.

Publications

• The Metalloprotease Meprin β Is an Alternative β-Secretase of APP. Front Mol Neurosci. 2017 Jan 5;9:159
  Becker-Pauly C, Pietrzik CU
  
• Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding. Cell Mol Life Sci. 2019 Aug;76(16):3193-3206
  Scharfenberg F, Armbrust F, Marengo L, Pietrzik C, Becker-Pauly C
  
• Tethering soluble meprin α in an enzyme complex to the cell surface affects IBD-associated genes. FASEB J. 2019 Jun;33(6):7490-7504
  Peters F, Scharfenberg F, Colmorgen C, Armbrust F, Wichert R, Arnold P, Potempa B, Potempa J, Pietrzik CU, Häsler R, Rosenstiel P, Becker-Pauly C
  
• The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ generation
  Armbrust F, Colmorgen C, Pietrzik CU, Becker-Pauly C
  
• The metalloprotease ADAMTS4 generates N-truncated Aβ4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease. Acta Neuropathol. 2019 Feb;137(2):239-257
  Walter S, Jumpertz T, Hüttenrauch M, Ogorek I, Gerber H, Storck SE, Zampar S, Dimitrov M, Lehmann S, Lepka K, Berndt C, Wiltfang J, Becker-Pauly C, Beher D, Pietrzik CU, Fraering PC, Wirths O, Weggen S
  
• Degradome of soluble ADAM10 and ADAM17 metalloproteases. Cell Mol Life Sci. 2020 Jan;77(2):331-350
  Scharfenberg F, Helbig A, Sammel M, Benzel J, Schlomann U, Peters F, Wichert R, Bettendorff M, Schmidt-Arras D, Rose-John S, Moali C, Lichtenthaler SF, Pietrzik CU, Bartsch JW, Tholey A, Becker-Pauly C
  
• Meprin β: A novel regulator of blood-brain barrier integrity. J Cereb Blood Flow Metab. 2020 Feb 16
  Gindorf M, Storck SE, Ohler A, Scharfenberg F, Becker-Pauly C, Pietrzik CU