Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia

Abstract

Down syndrome (DS) is one of the most frequent genetic abnormalities characterized by multiple pathological phenotypes. Indeed, currently life expectancy and quality of life for DS patients have improved, although with increasing age pathological dysfunctions are exacerbated and intellectual disability may lead to the development of Alzheimer's type dementia (AD). The neuropathology of DS is complex and includes the development of AD by middle age, altered free radical metabolism, and impaired mitochondrial function, both of which contribute to neuronal degeneration. Understanding the molecular basis that drives the development of AD is an intense field of research. Our laboratories are interested in understanding the role of oxidative stress as link between DS and AD. This review examines the current literature that showed oxidative damage in DS by identifying putative molecular pathways that play a central role in the neurodegenerative processes. In addition, considering the role of mitochondrial dysfunction in neurodegenerative phenomena, results demonstrating the involvement of impaired mitochondria in DS pathology could contribute a direct link between normal aging and development of AD-like dementia in DS patients.

Figure 1

Oxidative stress and down syndrome. Increased conditions of oxidative stress are caused by the overexpression of some of the genes encoded by Chr21. Among these, amyloid precursor protein (APP), copper-zinc superoxide dismutase (SOD1), and beta secretase (BACE2) can directly or indirectly lead to OS.

Figure 2

Putative adaptation to OS in down syndrome. OS occurs early in DS pathogenesis and progression. Accumulation of oxidative damage leads to severe phenotypes while the induction of compensatory mechanisms in response to chronic OS could result in “adaptation” and could contribute to improve the life span of DS subjects.