Reply to Lauren et al 2009
Kessels HW, Nguyen LN, Nabavi S, Malinow R.
Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer’s disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Laurén et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).
These results are consistent with those of Balducci et al, 2010 in PNAS and Calella et al, 2010 in EMBO Mol Med. However, overexpression of CT-100 does not only lead to increases in A-beta levels, but also other c-terminal fragments when cleaved by the secretases. Also, it is still not clear if overexpression of CT-100 produces the same species of A-beta oligomers as the synthetic preparation, which contains a ~15kDa and ~56kDa sized soluble oligomer. The work from Balducci et al provide stronger evidence that PrP may not have a role in Alzheimer’s disease in that addition of exogenous A-beta oligomers to a PrP -/- mouse still causes the animal to have a behavioral learning deficit.
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