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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and its socioeconomic impact is increasing as the population ages [1]
PrPC was significantly reduced in sporadic AD by a mean of 49% (p = 0.014) compared to the age matched controls (Figure 1A and B, Table 1) but there was no significant difference in Contactin 5 (CNTN5) between sporadic AD and controls (Figure 1C and D, Table 1)
There was no significant difference in the level of neuron-specific enolase (NSE) between the sporadic AD and control samples (Table 1), indicating that the lower PrPC in the sporadic AD samples was not caused by neuronal loss
Summary
Alzheimer’s disease (AD) is the most common form of dementia and its socioeconomic impact is increasing as the population ages [1]. AD is characterised pathologically by the formation of intracellular neurofibrillary tangles and extracellular amyloid plaques. Neurofibrillary tangles, composed of hyperphosphorylated and aggregated tau [3], initially appear in the entorhinal cortex and hippocampus, before the spread of tau pathology into other regions [4]. A number of rare autosomal dominant mutations in the genes encoding either APP or components of the c-secretase complex have been identified which cause early-onset, or familial, AD. The majority of AD patients, do not have such underlying genetic factors and, some risk factors have been identified (e.g. ageing and the e4 allele of the apolipoprotein E gene), the cause of these sporadic AD cases remains unknown
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