Description
Tracking the evolution of neuroinflammation in Down syndrome
Lisi Flores Aguilar1, M. Florencia Iulita2, Maria Torres3, Thomas Wisniewski4, Jorge Busciglio3, A. Claudio Cuello1
1McGill University, Montreal, Canada: 2Université de Montréal, Montreal, Canada
3University of California, Irvine, USA: 4New York University School of Medicine, USA
Clinical and experimental data support the concept that pre-clinical neuroinflammation may play a central role in the progression of Alzheimer's disease (AD) (1). Characterization of this neuroinflammatory process in humans is an unmet need.
AD is the main medical problem in adults with Down syndrome (DS). DS individuals exhibit early intraneuronal amyloid-β (Aβ) accumulation (2) and develop full-blown AD pathology in adulthood. We have recently reported an elevation of pro-inflammatory cytokines in plasma from DS individuals before the presentation of clinical AD that correlated with cognitive decline (3). We hypothesize that intraneuronal Aβ will unleash a neuroinflammatory process at incipient AD stages in DS. Thus, our main objective is to study such an inflammatory process as AD pathology evolves in DS.
Methods: Inflammatory markers in conditioned media (CM) of DS and control human fetal cortical cells was examined with a multiplex array (Eve Technologies) and ELISA (Abcam, Enzo LS). A qPCR inflammatory array (Qiagen) and individual qPCRs were performed using the frontal cortex of DS individuals (neonates and DS-AD adults) and age-matched controls.
Results: FGF1, G-CSF, IL-12, MDC, IL-1α, IL-4, MIP-1β, IL-6 and CCL-2 were significantly upregulated in the CM of DS fetal cortical cells. Elevation of inflammatory markers was also found in frontal cortex from individuals with DS and AD (IL-12, IL-6, CCL2, IL-18, IFN-B, TNFα, TGF-β). Interestingly, our preliminary PCR results revealed that the expression of inflammatory markers is more exacerbated at early stages of AD pathology in DS (neonates) compared to the clinical stage (DS-AD). We are currently extending the analysis to DS infants, DS adolescents and DS adults without AD.
Discussion: Our results support the occurrence of an early inflammatory process in DS which differs from the late neuroinflammation associated with the clinical stages of AD in DS.
Ref: 1. Cuello AC, Trends Pharm Sci. 2017; 2. Busciglio J, Neuron 2002; 3. Iulita MF, Alz & Dem. 2016
This project was supported by the CIHR (ACC) and the NIH (TW, JB).