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 (PrPC) has been implicated in the development of Alzheimer's disease (AD). PrPC 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 PrPC 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. PrPC 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). PrPC 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 PrPC 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). PrPC 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 PrPC in the DS brains compared to controls (p = 0.625). These data are consistent with a role for PrPC in regulating Aβ production and indicate that brain PrPC level may be important in influencing the onset and progression of sporadic AD.

Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPC), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution

“…Whitehouse et al measured PrP C in the frontal cortex of 24 sporadic AD brains vs. 24 age-matched controls and found a significant decreased of PrP C in AD brains. Interestingly, PrP C significantly inversely correlated with BACE1 activity, Aβ load, soluble Aβ, and insoluble Aβ and with the stage of disease, as indicated by Braak tangle stage (Whitehouse et al, 2013). The authors concluded that brain PrP C level may be important in influencing the onset and progression of sporadic AD (Whitehouse et al, 2013).…”

“…Of interest to us are the controversial issues in the literature linking Aβ oligomers and PrP C (Laurén et al, 2009; Nygaard and Strittmatter, 2009; Gunther and Striitmatter, 2010; Kessels et al, 2010; Barry et al, 2011; Saijo et al, 2011; Larson et al, 2012; Um et al, 2012; Chen et al, 2013; Kudo et al, 2013; Whitehouse et al, 2013; Younan et al, 2013). A few specific examples to make the point: Kudo et al showed that Prnp (-/-) mice are resistant to the neurotoxic effect of oligomeric Aβ in vivo and in vitro (Kudo et al, 2013).…”

Physiological Functions of the Cellular Prion Protein

“…Aβ accumulates during pathogenesis of Alzheimer's disease (AD) and PrP C reportedly acts as an inhibitor of β-secretase 1 (Parkin et al, 2007; Whitehouse et al, 2013), thereby reducing the amount of Aβ produced and suggesting that PrP C expression should protect against the development of AD. A feedback loop has also been proposed that consists of the APP intracellular domain (the other fragment produced by cleavage of sAPPβ) activating cellular tumour antigen p53, which subsequently upregulates PrP C expression, leading to further inhibition of β-secretase 1 activity (Vincent et al, 2009).…”

New light on prions: putative role of co-operation of PrPc and Aβ proteins in cognition

“…Authors of this study point out that a decreased level of PrP c results in a decreased zinc uptake within the synapses. Such condition results in an elevated synaptic zinc level, which favours binding Aβ oligomers to the NMDA receptors, and mediates the excitotoxicity [86]. In our opinion, it is more probable that an inverse correlation with Braak stage assessed tauopathy was caused by the elevation of Aβ and PrP c ratio, and its direct impact on tau expression.…”