Pattern of proteolytic processing of Amyloid Precursor Protein in Down syndrome

Abstract

AbstractBackgroundCurrently, it is estimated that 1 in 800 live births worldwide has Down syndrome (DS). In addition to the relationship with intellectual disability, DS is directly associated with a group of clinical manifestations resulting from premature aging, and may present patterns of comorbidities similar to those found in the elderly. Therefore, together with the greater number of years lived, there is an increased risk of developing Alzheimer's disease (AD) in DS, especially with regard to the interaction between pathogenic mechanisms related to cerebral amyloidogenesis and factors inherent to premature aging. Thus, this study aimed to investigate biological markers of AD in peripheral blood samples from adults and elderly individuals with DS and to compare them with individuals with normal karyotype, stratifying the groups according to the presence or absence of cognitive impairment.MethodA total sample of 123 individuals was recruited. The experimental group consisted of 31 adults and elderly individuals with DS. Two comparative groups were categorized according to euploid individuals (EU), being 23 elderly with AD (EUAD) and 69 adults with normal cognition (EUNC). The DS group was subclassified according to the occurrence of cognitive decline, DS without evidence of cognitive decline (DSNC) and DS with cognitive decline (DSAD). AD biomarkers were determined in platelets, including the Amyloid Precursor Protein ratio (APPr), established by the ratio between the 130‐ and 110kDA secreted peptides (sAPP), as well as the protein expression of APP‐secretases α (ADAM‐10), β (BACE‐1) and γ (PSEN1).ResultThe comparison between DSNC vs. EUNC, showed lower protein expression of APP secretases among individuals with DS. When observed groups with cognitive decline (i.e., DSAD vs. EUAD), the DSAD group showed lower expression of APP130 and 110kDa and BACE1 fragments, as well as increased levels of APPr compared to EUAD. It was also observed a 2.5‐fold decrease expression of APP130 in SDAD, compared to SDNC.ConclusionThese results demonstrate that people with DS may show different expression patterns of proteins involved in the amyloid cascade, detectable even in the absence of cognitive decline. However, more analysis is needed for these data to be confirmed.