Amyloidogenic biomarkers in Down syndrome

Author(s)

Jéssyka Maria de França Bram Monezi

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2023-06-22

Examining board members

Orestes Vicente Forlenza; Helio Elkis; Erika Cristina Pavarino; Wilson Araújo da Silva Junior

• Advisor: Orestes Vicente Forlenza; Leda Leme Talib

Abstract

Currently, it is estimated that 1 in every 1000 live births worldwide has Down syndrome (DS). Due to the genetic characteristics of this syndrome, it 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 concerning the interaction between the pathogenic mechanisms related to cerebral amyloidogenesis and the factors inherent to premature aging. Thus, this study aimed to investigate AD biological markers in peripheral blood samples from adults and elderly individuals with DS (n=82) and compare them with individuals with normal karyotype (n=99), stratifying the groups according to the presence or absence of cognitive impairment. The DS group was subclassified according to the occurrence of cognitive impairment and/or dementia, 55 SD without evidence of cognitive decline (DSNC) and 27 DS with cognitive decline (SDAD). Two comparative groups composed of euploid individuals were constituted, 23 elderly with AD (AD) and 76 adults and elderly with normal cognition (Control). AD biomarkers were determined in platelets and plasma, including the Amyloid Precursor Protein ratio (APPr), established by the ratio between secreted 130- and 110kDA peptides (sAPP), the protein expression of ADAM10, BACE1 and PSEN1, as well as levels of A40, A42 and between A42/A40 ratio. Results demonstrated increased APPr for both DS groups compared to euploids. On the other hand, lower expression of the APP130 and 110kDa fragments was observed in both DSNC and DSAD, and both fragments showed levels between 6 and 7 times lower in DSAD compared to DSNC. About secretases, a reduction in the expression of ADAM10, BACE1 and PSEN1 was observed in individuals with DS compared to euploids, with no difference between DSNC and DSAD. Regarding the euploid groups, the AD subgroup had higher levels of BACE1 when compared to the Control. Regarding the A peptide, a higher plasma level of A40 and a lower A42/A40 ratio were identified for both DSNC and DSAD groups, in relation to the Control. Using a predictive classification tree and regression model (CART), the combination of APP130kDa biomarkers and the A42/A40 ratio proved to be relevant for separating groups in terms of cognitive impairment, through the classification APP130kDa < 0 .9, A42/A40 0.409 and APP130 0.77 or APP130kDa < 0.9, A42/A40 < 0.409, with a diagnostic accuracy of 79.9% (sensitivity: 30.6%; specificity: 98.5%; Kappa concordance coefficient: 0.365). The results of this study demonstrate that people with DS can show different patterns of expression of the proteins involved in the amyloid cascade, detectable even in the absence of cognitive decline, suggesting DS as a good predictive model of AD (AU)

• FAPESP's process: 18/13398-6 - Biomarkers in Down Syndrome
• Grantee: Jessyka Maria de França Bram Monezi
• Support Opportunities: Scholarships in Brazil - Doctorate