Abstract
Down syndrome (DS) subjects are more likely to develop the clinical features of Alzheimer’s disease (AD) very early in the disease process due to the additional impact of neuroinflammation and because of activation of innate immunity. Many factors involved in the neuropathology of AD in DS, including epigenetic factors, innate immunity and impaired haematopoiesis, contribute significantly towards the pathophysiology and the enhanced ageing processes seen in DS and as a consequence of the triplication of genes RUNX1, S100β and OLIG2, together with the influence of proteins that collectively protect from cellular defects and inflammation, which include hepcidin, ferritin, IL-6 and TREM2. This study is aimed at determining whether genetic variants and inflammatory proteins are involved in haematopoiesis and cellular processes in DS compared with age-matched control participants, particularly with respect to neuroinflammation and accelerated ageing. Serum protein levels from DS, AD and control participants were measured by enzyme-linked immunosorbent assay (ELISA). Blood smears and post-mortem brain samples from AD and DS subjects were analysed by immunohistochemistry. RUNX1 mRNA expression was analysed by RT-PCR and in situ hybridisation in mouse tissues. Our results suggest that hepcidin, S100β and TREM2 play a critical role in survival and proliferation of glial cells through a common shared pathway. Blood smear analysis showed the presence of RUNX1 in megakaryocytes and platelets, implying participation in myeloid cell development. In contrast, hepcidin was expressed in erythrocytes and in platelets, suggesting a means of possible entry into the brain parenchyma via the choroid plexus (CP). The gene product of RUNX1 and hepcidin both play a critical role in haematopoiesis in DS. We propose that soluble TREM2, S100β and hepcidin can migrate from the periphery via the CP, modulate the blood–brain immune axis in DS and could form an important and hitherto neglected avenue for possible therapeutic interventions to reduce plaque formation.
Highlights
Down syndrome (DS) is the leading genetic cause of intellectual disabilities in liveborn infants and is caused by the presence of an extra copy of chromosome 21 (Hsa21) [1,2,3].People with DS have characteristic phenotypes including growth retardation, cognitive impairments, premature ageing, abnormal haematopoiesis, various forms of leukaemia and immune disorders [1,2,3]
Ferritin, superoxide dismutase 1 (SOD1), S100β, IL-6 and triggering receptor expressed on myeloid cells 2 (TREM2) expression in serum and post-mortem brain samples to determine the crosstalk between inflammation and iron dysregulation in normal ageing and in DS pathology and to ascertain how these changes in neuroinflammation could play a role in the acceleration of ageing in DS
We further investigated white matter (WM) close to the blood vessels (BV) in the DS brain and found large numbers of Iba1-positive microglia, close to the blood vessels, that could be involved in the clearing process of damaged oligodendrocytes, and some TREM2-positive macrophages seem to have entered from blood vessels (Figure 5E)
Summary
People with DS have characteristic phenotypes including growth retardation, cognitive impairments, premature ageing, abnormal haematopoiesis, various forms of leukaemia and immune disorders [1,2,3]. There are many factors likely to be involved in the development and progression of the neuropathology of Alzheimer’s disease (AD) and in the enhanced ageing processes in DS, including epigenetic factors, innate immunity and impaired haematopoiesis [3,4,5,6]. The mechanism of the early onset of AD pathology in DS is not fully understood, but the over-expression of certain genes on Hsa, in the. Hsa gene expression do occur in trisomy 21 (T21) [10,11].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
