In response to Kessels et al
Juha Laurén1, David A. Gimbel1, Haakon B. Nygaard1, John W. Gilbert1 & Stephen M. Strittmatter1
Amyloid-? oligomers are correlated with Alzheimer’s disease progression and suppress synaptic plasticity1, 2, 3. Through unbiased expression cloning, we identified cellular prion protein (PrPC) as an amyloid-? oligomer binding protein4. PrPC was necessary for acute amyloid-?(1?42) (A?42) oligomer suppression of synaptic plasticity4; thus, it becomes critical to explore the importance of PrPC in a range of Alzheimer’s-disease-related deficits. Transgenic Alzheimer’s disease model mice show deficits of spatial learning and memory5, so the most direct assessment of PrPC will monitor memory in transgenic Alzheimer’s disease model mice deficient for PrPC. In this paradigm, amyloid-? species are produced endogenously and the brain is exposed chronically over months. Recently, we have found that deletion of PrPC from APPswe/PSen1?E9 transgenic mice restores spatial learning and memory without altering amyloid-?6. Furthermore, the early death, synapse loss and serotonin axonal degeneration of transgenic Alzheimer’s disease mice require PrPC (ref. 6). Kessels et al.7 examine PrPC in alternative paradigms.
[...] Lauren et al reply 12 August, August, Nature, Neuroscience [...]
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Most of the suggestions postulated as differences between Lauren et al’s and Kessels et al’s work in this reply are in regard to different concentrations of A-beta being used. However, both studies appear to use 500nM of A-beta 42 according to each of their methods. Though, A-beta has a notorious reputation for being sticky to anything it comes in contact with, including 1.5 mL eppendorf tubes and perfusion tubing. It is possible that the way the A-beta was handled may have changed the effective concentration of A-beta at the slice being recorded from.
The link to Alzforum.org used as support in regard to other groups finding that PrP is mediating A-beta-induced synaptic effects is a comment from Walsh et al in regard to a paper (Balducci et al, 2010) that has conflicting behavioral results with Lauren et al. More curious is the lack of reference to these “consistent data” in a Nature News article about PrP and A-beta (http://www.nature.com/news/2010/100824/full/4661031a.html)
However, a very interesting proposition was made at the end of this reply: PrP may not be THE receptor for A-beta, but may help concentrate A-beta at the surface of neurons, thus increasing it’s functional activity via the true receptor for A-beta. PrP is primarily an intracellular protein, though some studies suggest that PrP can exist extracellularly in normal/healthy conditions. This adds a level of complication to the story on the possible existence of a receptor for extracellular prion protein bound to A-beta, or a complex mechanism on how extracellular A-beta can pass through the plasma membrane to bind with intracellular PrP.
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