In receptor binding terminology both receptor and acceptor

In receptor binding terminology, both receptor and acceptor contain a receptive site for the ligand, although only the receptor induces a biological function. Moreover, the acceptor lacks an endogenous ligand. Many proteins have been described as receptors for toxic Aβ assemblies, implying a designed physiological function. It is possible that toxicity is linked to hijacking of a functional interaction with other Aβ assemblies, but until this is demonstrated the candidates are best described as acceptors for toxic Aβ assemblies. To date, the majority of research on the prion protein (PrP):Aβ interaction has focused on the toxic signaling cascades rather than physiological or beneficial roles. Two possible functions of PrP as an Aβ receptor have been suggested: 1) as a facilitator of the low-density lipoprotein receptor–related protein 1 mediated Aβ monomer transcytosis out of the AG-490 through the blood-brain barrier; and 2) as a protector against Aβ-induced cell death by neutralizing oligomeric Aβ , , , , . If the Aβ:PrP interaction has a function, it will no doubt unravel as we better understand the true physiological role of PrP . More research is needed to confirm the consequences of Aβ assemblies binding to PrP, as this will be crucial to develop new therapies targeting the interaction or its downstream effectors. PrP-Mediated Aβ Toxicity
Controversy and Confirmation
Aβ:PrP Interaction
Other Aβ Acceptors
Future Focus After initial scepticism and controversy, the PrP:Aβ interaction is now becoming accepted as a significant player in Aβ-mediated toxicity in vitro and in vivo. Its high affinity has not been disputed, and the molecular basis of this complex interaction is now being unraveled. Care needs to be taken to ensure that experiments are carried out under the most physiological conditions possible and are described in such a way that they can be faithfully reproduced. More details of the structural basis of the interaction and mechanisms of neurotoxicity and concrete explanations for reported discrepancies among publications are required to truly understand the phenomenon. It would aid the field if researchers reported both positive and negative results together to help establish the reasons for PrP-dependent and PrP-independent toxicity. If the hypothesis that PrP is involved in AD cannot be falsified, experimental medicine studies could be considered. The relevance of this interaction to the clinical features and progression of human AD can be firmly established only through clinical trials of drug candidates that block the interaction or downstream toxicity. This in turn could determine the suitability of individual animal models to AD drug discovery. A humanized anti-PrP mAb has now been developed for treatment of prion disease, and a preclinical study in live rats demonstrated that intravascular administration of this antibody can block Aβ-induced inhibition of synaptic plasticity without causing acute toxicity (67), suggesting it might be suitable for clinical trials in AD should it have a satisfactory safety profile. Likewise, a phase Ib study for a potent inhibitor of the src family of kinases, including Fyn, has recently been completed 95, 96 with a phase IIa trial currently underway. Confirmation of efficacy in human trials would firmly establish a role for PrPC in AD. It is unlikely that any therapeutic would reverse all symptoms in patients with AD, but blocking acute synaptotoxic effects may have an immediate measurable effect in memory and cognitive function. The second question of whether this then slowed rates of neurodegeneration would require major clinical trials. A confirmed disease-modifying therapeutic in the AD field would be a huge step forward after so many disappointments. While the PrP:Aβ interaction was identified only a few years ago, it is hoped that direct examination of its true relevance to AD via experimental medicine may not be too far away.