. Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice. J Neurosci. 2009 Feb 18;29(7):1977-86. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. The authors are well known for their sound experimental procedures. In this study, they crossbred Tg mice that overexpress APP and NEP. The transgene expression was driven by PDGF and CamKII promoters, respectively.

    This overexpression paradigm employed is very much artificial: unphysiological overproduction of APP, APPs, AICD in PDGF-expressing cells and unwanted genomic disruption in the case of APP Tg mice, any of which can affect the cognitive phenotypes. In addition, the Tg mice by definition are not perfect models for AD because they fail to reconstitute two indispensable pathologies, i.e., tauopathy and neurodegeneration. Something is still missing.

    Under normal conditions, APP and NEP colocalize well in the brain. It is therefore of particular interest to examine their colocalization in the double-Tg mice, for which distinct promoters were used. No proteases can degrade their substrates unless they come across each other in vivo. For the catabolism of Aβ, secretary vesicles and synapses are the important locations. Generally speaking, single Tg mice are already artificial, so double Tg mice can be superartificial. This is why we crossed APP-Tg mice with NEP-KO mice and obtained essentially opposite results (Huang et al., 2006).

    Do the Aβ trimer and Aβ* that the authors observed represent relevant primary pathogenic agents in AD brains? Is Aβ* really Aβ homo-oligomer? I guess there is some discrepancy between this paper and the 2008 Nat Med paper by the Selkoe group (Shankar et al., 2008).

    Unfortunately, some references are cited in a misleading manner, for instance, Kanemitsu et al., 2003.

    References:

    . Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem. 2006 Jun 30;281(26):17941-51. Epub 2006 Apr 24 PubMed.

    . Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):837-42. PubMed.

    . Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci Lett. 2003 Oct 23;350(2):113-6. PubMed.