Dataset Information

Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease.

ABSTRACT: BACKGROUND:Down syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid-? peptides and tau (as their accumulation is a characteristic feature of AD) and cytokines (as the inflammatory response has been implicated in AD development, and immune dysfunction is common in DS). METHODS:We used ultrasensitive assays to compare plasma concentrations of the amyloid-? peptides A?40 and A?42, total tau (t-tau), and the cytokines IL1?, IL10, IL6, and TNF? between adults with DS (n =?31), adults with sAD (n =?27), and controls age-matched to the group with DS (n =?27), and explored relationships between molecular concentrations and with age within each group. In the group with DS, we also explored relationships with neurofilament light (NfL) concentration, due to its potential use as a biomarker for AD in DS. RESULTS:A?40, A?42, and IL1? concentrations were higher in DS, with a higher A?42/A?40 ratio in controls. The group with DS showed moderate positive associations between concentrations of t-tau and both A?42 and IL1?. Only NfL concentration in the group with DS showed a significant positive association with age. CONCLUSIONS:Concentrations of A?40 and A?42 were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the A?42/A?40 ratio between those with DS and sAD may indicate similar processing and deposition of A?40 and A?42 in these groups. Higher concentrations of IL1? in DS may reflect an increased vulnerability to infections and/or an increased prevalence of autoimmune disorders, while the positive association between IL1? and t-tau in DS may indicate IL1? is associated with neurodegeneration. Finally, NfL concentration may be the most suitable biomarker for dementia progression in DS. The identification of such a biomarker is important to improve the detection of dementia and monitor its progression, and for designing clinical intervention studies.

SUBMITTER: Startin CM

PROVIDER: S-EPMC6429702 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease.

Startin Carla M CM Ashton Nicholas J NJ Hamburg Sarah S Hithersay Rosalyn R Wiseman Frances K FK Mok Kin Y KY Hardy John J Lleó Alberto A Lovestone Simon S Parnetti Lucilla L Zetterberg Henrik H Hye Abdul A Strydom André A

Alzheimer's research & therapy 20190321 1

<h4>Background</h4>Down syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid-β peptides and tau (as their accumulation is a c ...[more]

PMID: 30902060

Similar Datasets

Project description:In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more 'aggressive' form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.

Project description:Alzheimer's disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD.We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer's disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer's disease (sAD); and three control individuals without dementia. The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods.Neurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. Relative to the control neurons, neurons derived from patients with fAD and patients with sAD exhibited higher levels of extracellular amyloid-? 1-40 (A?1-40) and amyloid-? 1-42 (A?1-42). However, significantly increased A?1-42/A?1-40 ratios, which is one of the pathological markers of fAD, were observed only in samples of patients with fAD. Additionally, we detected increased levels of active glycogen synthase kinase 3 ?, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both fAD- and sAD-derived neurons.On the basis of the experiments we performed, we can conclude there is no evident difference except secreted A?1-40 levels in phenotype between fAD and sAD samples. To our knowledge, this is the first study in which the hyperphosphorylation of TAU protein has been compared in fAD and sAD iPSC-derived neurons. Our findings demonstrate that iPSC technology is suitable to model both fAD and sAD and may provide a platform for developing new treatment strategies for these conditions.

Dataset Information

Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease.

Publications

Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure