Abstract
Current evidence indicating a role of the human prion protein (PrP) in amyloid-beta (Aβ) formation or a synergistic effect between Aβ and prion pathology remains controversial. Conflicting results also concern the frequency of the association between the two protein misfolding disorders and the issue of whether the apolipoprotein E gene (APOE) and the prion protein gene (PRNP), the major modifiers of Aβ- and PrP-related pathologies, also have a pathogenic role in other proteinopathies, including tau neurofibrillary degeneration. Here, we thoroughly characterized the Alzheimer’s disease/primary age-related tauopathy (AD/PART) spectrum in a series of 450 cases with definite sporadic or genetic Creutzfeldt-Jakob disease (CJD). Moreover, we analyzed: (i) the effect of variables known to affect CJD pathogenesis and the co-occurring Aβ- and tau-related pathologies; (II) the influence of APOE genotype on CJD pathology, and (III) the effect of AD/PART co-pathology on the clinical CJD phenotype. AD/PART characterized 74% of CJD brains, with 53.3% and 8.2% showing low or intermediate-high levels of AD pathology, and 12.4 and 11.8% definite or possible PART. There was no significant correlation between variables affecting CJD (i.e., disease subtype, prion strain, PRNP genotype) and those defining the AD/PART spectrum (i.e., ABC score, Thal phase, prevalence of CAA and Braak stage), and no difference in the distribution of APOE ε4 and ε2 genotypes among CJD subtypes. Moreover, AD/PART co-pathology did not significantly affect the clinical presentation of typical CJD, except for a tendency to increase the frequency of cognitive symptoms. Altogether, the present results seem to exclude an increased prevalence AD/PART co-pathology in sporadic and genetic CJD, and indicate that largely independent pathogenic mechanisms drive AD/PART and CJD pathology even when they coexist in the same brain.
Highlights
IntroductionCreutzfeldt-Jakob disease (CJD), the most common human prion disease with an estimated incidence of 2 cases per million, comprises several clinical-pathological phenotypes and uniquely occurs in three forms with apparent distinct etiologies [6, 38]
Creutzfeldt-Jakob disease (CJD) and Alzheimer’s disease (AD) are protein-misfolding disorders characterized by auto-propagation and tissue deposition of protein aggregates leading to progressive neuronal dysfunction and neurodegeneration.CJD, the most common human prion disease with an estimated incidence of 2 cases per million, comprises several clinical-pathological phenotypes and uniquely occurs in three forms with apparent distinct etiologies [6, 38]
Current classification of sporadic (s) CJD, the most common form, includes six major disease subtypes that are primarily determined by the combination of the genotype at the polymorphic codon 129 of prion protein gene (PRNP), encoding for methionine (M) or valine (V), with either one of two types (1 and 2) of misfolded prion protein (PrPSc) that differ in the size (21 and 19 kDa) of their protease-resistant core [55, 56, 58, 59]
Summary
CJD, the most common human prion disease with an estimated incidence of 2 cases per million, comprises several clinical-pathological phenotypes and uniquely occurs in three forms with apparent distinct etiologies [6, 38]. They include sporadic cases of unknown origin, a genetic form linked to mutations in the prion protein gene, PRNP, and an infectious form acquired through medical procedures or contaminated food. The pathological hallmarks of AD comprise extracellular amyloid plaques consisting of aggregated amyloid beta (Aβ) peptide and intracellular neurofibrillary degeneration (NF), made of paired helical filaments of hyperphosphorylated tau (p-tau) forming neurofibrillary tangles (NFTs), neuropil threads (NThs) and abnormal neurites (Nts)
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