Prion Protein Keeps β-secretase in Check

Alzheimer disease and the prion diseases share some features, with both conditions associated with early onset dementia. But they may be more interconnected than previously thought, according to results from Nigel Hooper and colleagues at the University of Leeds, England. In the June 15 edition of PNAS online, Hooper and colleagues show that the prion protein (PrP) inhibits β-secretase cleavage of the amyloid precursor protein and puts the brakes on the production of amyloid-β (Aβ) peptides both in vitro and in vivo.

The findings may have implications for both AD and transmissible spongiform encephalopathies (TSEs), otherwise known as prion diseases. A PrP gene polymorphism (Val/Met-129) has been identified as a risk factor for early onset AD (see Alzgene entry for PRNP, showing the PrP gene currently ranking twenty-seventh in terms of strength of association with AD). Hooper and coworkers present some evidence that the risk-associated Met allele may boost Aβ production in mice. They also show that mutant TSE-causing prion proteins fail to inhibit β cleavage and that prion-infected mice have elevated Aβ levels in the brain.

β-secretase catalyses the first cut of membrane-bound amyloid precursor protein (APP), releasing a soluble ectodomain and leaving a fragment that gets further processed to Aβ. To ask if PrP affected APP processing, first author Edward Parkin overexpressed the normal form of the prion protein in SH-SY5Y cells expressing APP, or overexpressing β-secretase. He found that in both cases, the cells almost completely lost production of the β-secretase product sAPPβ, and output of Aβ peptides was inhibited by 97 percent or more. The investigators corroborated the inhibitory potential of cellular prion (PrPc) with siRNA studies, where knocking down the expression of endogenous PrPc in SH-SY5Y cells led to an increase in Aβ secretion. The same result was seen in vivo in PrPc knockout mice, where levels of brain Aβ peptides were significantly increased compared to their wild-type counterparts.

How does PrP inhibit the β cleavage of APP? It did not appear to alter BACE expression, nor did PrP compete with APP for processing by the enzyme. The investigators evaluated a variety of PrP constructs for their effects on production of sAPPβ fragment, a direct measure of β-secretase activity in cultured cells. Only full-length, wild-type PrP, or PrP with an internal deletion of a set of copper-binding octapeptide repeats, maintained their ability to inhibit APP processing. Further experiments showed that the N-terminal polybasic region was critical for the inhibitory activity, as was membrane localization and the protein’s presence in cholesterol-rich lipid raft regions of the membrane. Co-immunoprecipitation showed that PrP and BACE were directly associated, but the researchers did not find evidence for direct inhibition of BACE by PrP. Instead, their data show that PrP needs to bind to glycosaminoglycans (GAG), which also bind to BACE. They speculate that the interaction of a PrP-GAG complex with BACE interferes with APP access to the enzyme.

Interestingly, two disease-causing mutants of PrP, the insertion mutant PG14 and A116V, failed to inhibit Aβ production in SH-SY5Y cells, leading the researchers to check Aβ levels in two strains of mice infected with pathogenic prions. In both cases, the mice had higher levels of Aβ in their brains: Aβ1-42 was significantly higher in both strains, while Aβ1-40 was also increased in one of the strains. “This result suggests that during prion disease, when PrPc undergoes a conformational conversion to PrPsc, the inhibition of β-cleavage of APP might be lost, resulting in an increase in the amount of Aβ,” the researchers write.

What of the role of PrP in AD? To test the effects of the polymorphism (Val/Met-129) that is associated with an increased risk of Alzheimer disease, the researchers looked at Aβ production in mice with their endogenous PrP gene replaced by either the V or M form of human PrP. They observed a small but statistically significant increase in Aβ1-40 in MM mice compared to VV. There was no difference in levels of Aβ1-42.

It remains to be seen whether the increase in Aβ seen in mice with the human MM genotype explains the slightly higher risk of AD in people, the authors write. They point out that even small changes in Aβ production, sustained over decades, could significantly hasten or slow the deposition of amyloid in the brain.

The results could also affect thinking about new treatments for both diseases. As the authors conclude, “These observations raise significant questions about whether depletion of PrPc is a sound therapeutic approach [see ARF related news story] for TSEs, but suggest that pharmacological interventions that mimic the effect of PrPc inhibiting the β-secretase cleavage of APP may represent a therapeutic approach for AD.”—Pat McCaffrey.

Reference:
Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates {beta}-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 15; [Epub ahead of print] Abstract

Comments

  1. This is a very interesting work. It has been shown that the most common misdiagnosis of Creutzfeldt-Jakob disease (CJD) is Alzheimer disease (1). The symptoms and pathology of both diseases overlap (2). There can be spongy changes in Alzheimer disease patients while senile plaques are also found in CJD patients (2). The causes of the two diseases might overlap as well: epidemiological evidence suggests that people eating meat more than four times a week for a prolonged period have a three times higher chance of suffering a dementia than long-time vegetarians (3), although such a conclusion remains to be verified. A previous study also showed that the brains of the young people who died from the new CJD variant in Britain even look like Alzheimer brains (4). All this evidence indicates there could be some interaction between CJD and Alzheimer disease; however, no study has yet shown a direct link between these two diseases.

    In the current issue of PNAS, Edward Parkin et al. report that the wild-type prion protein, whose mutant form is the culprit in CJD, prevents β-site APP secretase (BACE1) from accessing its substrate APP, which leads to a decrease in Aβ production (5). In other words, PrPc inhibits the β-secretase cleavage of APP with no effect on either BACE1 level or enzymatic activity. Further, the authors provide evidence that the polybasic N-terminus of PrPc and its localization to lipid rafts are required for the inhibition of β-secretase, suggesting that such regulation might depend on the localization of prion protein to the cholesterol-rich lipid rafts and be mediated by the interaction between the N-terminal polybasic region of prion protein and glycosaminoglycans (5). The actual mechanism, though yet to be confirmed, suggests that prion protein might have a normal cellular function as a lipid raft modulator. The study also reveals a potential link between CJD and Alzheimer disease: the mutant prion, which is involved in CJD, fails to have a similar effect as its wild-type counterpart does, indicating loss of function of endogenous prion protein could unleash BACE1 to access APP and therefore increase Aβ production. If this is true, it explains why CJD and Alzheimer disease are so alike.

    References:

    Harrison PJ, Roberts GW. "Life, Jim, but not as we know it"? Transmissible dementias and the prion protein. Br J Psychiatry. 1991 Apr;158:457-70. PubMed.

    Brown P. Central nervous system amyloidoses: a comparison of Alzheimer's disease and Creutzfeldt-Jakob disease. Neurology. 1989 Aug;39(8):1103-5. PubMed.

    Giem P, Beeson WL, Fraser GE. The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study. Neuroepidemiology. 1993;12(1):28-36. PubMed.

    Liberski PP. Amyloid plaques in transmissible spongiform encephalopathies (prion diseases). Folia Neuropathol. 2004;42 Suppl B:109-19. PubMed.

    Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7. PubMed.

    View all comments by Yong Shen

  2. The paper by Parkin et al. is of extreme interest to the community. Since the physiological function of both proteins APP and PrP is still under intense discussion, the data presented in the paper show nicely this interaction.

    As known from the glial cell line-derived neurotrophic factor (GDNF) and its GPI-anchored dimeric receptor (GFRa1), which transduces the information intracellularly via RET, there are also parallels for PrP and APP. Does PrP function as a GPI-anchored receptor which transduces the information by influencing APP cleavage or multimerization? What is the factor binding to PrP primarily?

    View all comments by Jens Pahnke

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References

News Citations

  1. Following Footsteps of AD Vaccination: Passive Shots Against Prions Protect Mice

Paper Citations

  1. Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7. PubMed.

External Citations

  1. PRNP

Further Reading

Papers

  1. Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7. PubMed.

Primary Papers

  1. Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7. PubMed.

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