Affiliations: [a]
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Goettingen, Germany
| [b]
German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany
| [c]
Department of iBiMED, Medical Sciences, University of Aveiro, Aveiro, Portugal
| [d]
Max Planck Institute of Experimental Medicine, Proteomics Group, Goettingen, Germany
Correspondence:
[*]
Correspondence to: Oliver Wirths, PhD, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, von-Siebold-Str. 5, 37075 Goettingen, Germany. Tel.: +49 551 3910290; E-mail [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: In sporadic Alzheimer’s disease (AD), an imbalance between production and clearance of amyloid-β (Aβ) peptides seems to account for enhanced Aβ accumulation. The metalloprotease neprilysin (NEP) is an important Aβ degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aβ peptides such as Aβ1-40 and Aβ1-42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aβ species such as the common variant Aβ4-42. In the present report, we confirmed the degradation of Aβ4-x species by neprilysin using in vitro digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aβ4-42 peptides with homozygous NEP-knock-out mice (NEP-/-), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aβ levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD.
