Editors' ChoiceAlzheimer’s Disease

Doubling-down on prion protein function in Alzheimer’s disease

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaay3567
DOI: 10.1126/scitranslmed.aay3567


The prion protein functions as a carrier for delivering Aβ to exosomes during Alzheimer’s disease.

Prion protein (PrP) misfolding is widely recognized as the causative event in transmissible prion diseases (PrDs); however, PrP has also been proposed to play a role in Alzheimer’s disease (AD) pathogenesis. Proposed roles of PrP in AD include stimulating amyloid deposition and transduction of toxic signals through binding to the AD-associated β-amyloid (Aβ) peptide. Furthermore, PrD comorbidities include AD-like neuropathological changes, suggesting that PrD might promote formation of AD-like pathology.

To investigate the PrD-AD co-pathologies, Qin et al. created a “dual disease” model. The authors crossed two mouse lines: one representing genetic AD and one that develops genetic PrD, caused by mutations within the APP/PS1 and prnp genes, respectively. Although they did not find a difference in the propensity of mutant PrP to promote Aβ plaque deposition compared with wild-type animals, they did identify a previously unreported function of PrP. The Aβ plaques produced in the mutant PrP mice, and in mice lacking PrP, showed a greater ratio of intracellular to extracellular staining. Further investigation found wild-type PrP could bind to and deliver intraneuronal Aβ to exosomes for secretion. The inclusion of PrP within Aβ plaques was proposed to be a byproduct of this carrier function. The authors suggest that the newly identified carrier function is not mutually exclusive from previously identified functions, as each depends upon the ability of PrP to bind Aβ.

With plaque burden still evident in the PrP knock-out AD mouse models, the suitability of PrP as a therapeutic target for AD remains to be determined. However, other studies have shown that although PrP knock-down late in disease has little impact on plaque pathology, it does recover behavioral and synaptic function. Changing the intra-/extra-cellular location of Aβ deposition by altering its trafficking may be an explanation for the observed benefits of PrP loss. Targeting the pathways by which Aβ is excreted from cells and the binding partners involved may present an interesting strategy for therapeutic investigation.

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