Age-Related Neurodegeneration and Memory Loss in Down Syndrome

Abstract

Down syndrome (DS) is a condition where a complete or segmental chromosome 21 trisomy causes variable intellectual disability, and progressive memory loss and neurodegeneration with age. Many research groups have examined development of the brain in DS individuals, but studies on age-related changes should also be considered, with the increased lifespan observed in DS. DS leads to pathological hallmarks of Alzheimer's disease (AD) by 40 or 50 years of age. Progressive age-related memory deficits occurring in both AD and in DS have been connected to degeneration of several neuronal populations, but mechanisms are not fully elucidated. Inflammation and oxidative stress are early events in DS pathology, and focusing on these pathways may lead to development of successful intervention strategies for AD associated with DS. Here we discuss recent findings and potential treatment avenues regarding development of AD neuropathology and memory loss in DS.

Exosomal biomarkers in Down syndrome and Alzheimer's disease

“…Individuals with DS concurrently display enhanced microglial activation (Head et al 2016; Wilcock and Griffin 2013; Wilcock et al 2015), elevated oxidative stress, and mitochondrial dysfunction (Pagano and Castello 2012; Perluigi and Butterfield 2012). Collectively, these pathological hallmarks forge a pathway to AD in people with DS (DS-AD) leading to widespread and progressive neurodegeneration of basal forebrain cholinergic neurons (BFCNs), locus coeruleus (LC) noradrenergic (NE) neurons, certain hippocampal neuronal populations (Lockrow et al 2012; Millan Sanchez et al 2012; Salehi et al 2009), and neurons in certain cortical areas (Sadowski et al 1999; Teipel et al 2004), similar to the neurodegeneration observed in idiopathic AD (Wisniewski et al 1985). …”

“…Thus, oxidative stress is a major etiological factor on the pathway to DS-AD (Pagano and Castello 2012). The superoxide dismutase 1 ( SOD1 ) gene is encoded on Hsa21, within the so called Down syndrome critical region (DSCR) (Antonarakis 1998) and has been shown to have up to 50% increased activity in all DS tissues examined, including the brain (Sinet 1992), as well as in DS mouse models (Lockrow et al 2012). The levels of SOD1 protein and mRNA are particularly high in hippocampal pyramidal neurons in DS, which are especially susceptible to the degenerative processes that occur in DS-AD (Furuta et al 1995).…”

“…Inflammation is well-known to be a core pathological component of AD (Wilcock and Griffin 2013; Wilcock et al 2015), but the role of central and peripheral immune functions in people with DS on the path to DS-AD needs further study. Rampant neuroinflammation, including activation of both microglia and astrocytes, is a hallmark in the DS brain, as well as in DS mouse models (Lockrow et al 2012; Wilcock et al, 2013; Hartley et al, 2015). Circulating levels of inflammatory cytokines are also increased in blood isolated from people with DS (Rodrigues et al 2014), and the inflammatory markers correlate with other AD biomarkers in adults with DS (Naude et al 2015).…”

Evidence of altered age-related brain cytoarchitecture in mouse models of down syndrome: a diffusional kurtosis imaging study

“…Among them, the Ts65Dn (TS) model carries trisomic segments of mouse chromosome 16 that contain regions orthologous to human chromosome 21, and share some DS-relevant behavioral and morphological features (11,12). The TS model has been widely used for the study of age-related neurodegeneration and cognitive impairments parallel to those seen in the brain of DS individuals (13, 14). These mice exhibit memory and learning deficits associated with progressive loss of basal forebrain cholinergic neurons (15–17) and reduced hippocampal long-term potentiation (LTP) and increased long-term depression (LTD) (18,19).…”

Efficacy of selected treadmill training programme on oxidative stress in adolescents with Down syndrome

“…Research on this topic may be of great interest since oxidative damage has been proposed as a pathogenic mechanism of atherosclerosis, cell ageing, neurodegeneration [2], carcinogenic events and immunological disorders in this population [3]. Oxidative stress is a term used to describe the effect of oxidation in which an abnormal level of reactive oxygen species, such as free radicals (e.g.…”