. 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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  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:

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

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

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

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

    . 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