title: Prion protein is decreased in Alzheimer's brain and inversely correlates with BACE1 activity, amyloid-β levels and Braak stage.
abstract: The cellular prion protein (PrP(C)) has been implicated in the development of Alzheimer's disease (AD). PrP(C) decreases amyloid-β (Aβ) production, which is involved in AD pathogenesis, by inhibiting β-secretase (BACE1) activity. Contactin 5 (CNTN5) has also been implicated in the development of AD by a genome-wide association study. Here we measured PrP(C) and CNTN5 in frontal cortex samples from 24 sporadic AD and 24 age-matched control brains and correlated the expression of these proteins with markers of AD. PrP(C) was decreased in sporadic AD compared to controls (by 49%, p = 0.014) but there was no difference in CNTN5 between sporadic AD and controls (p = 0.217). PrP(C) significantly inversely correlated with BACE1 activity (rs = -0.358, p = 0.006), Aβ load (rs = -0.456, p = 0.001), soluble Aβ (rs = -0.283, p = 0.026) and insoluble Aβ (rs = -0.353, p = 0.007) and PrP(C) also significantly inversely correlated with the stage of disease, as indicated by Braak tangle stage (rs = -0.377, p = 0.007). CNTN5 did not correlate with Aβ load (rs = 0.040, p = 0.393), soluble Aβ (rs = 0.113, p = 0.223) or insoluble Aβ (rs = 0.169, p = 0.125). PrP(C) was also measured in frontal cortex samples from 9 Down's syndrome (DS) and 8 age-matched control brains. In contrast to sporadic AD, there was no difference in PrP(C) in the DS brains compared to controls (p = 0.625). These data are consistent with a role for PrP(C) in regulating Aβ production and indicate that brain PrP(C) level may be important in influencing the onset and progression of sporadic AD.
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Isobel J
authors.initials: IJ
authors.lastname: Whitehouse
authors.forename: J Scott
authors.initials: JS
authors.lastname: Miners
authors.forename: Elizabeth B C
authors.initials: EB
authors.lastname: Glennon
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Katherine A B
authors.initials: KA
authors.lastname: Kellett
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Hooper
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D058966:Contactins / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011328:Prions / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D058966:Contactins; D011328:Prions; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human