Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

Abstract

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.

Catechins as a Potential Dietary Supplementation in Prevention of Comorbidities Linked with Down Syndrome

“…DS, the most common chromosome abnormality among newborns (trisomy 21), has an estimated prevalence of 1 in 800 live births [ 42 ]. It is therefore the most common genetic developmental disorder.…”

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

“…Seventy-six duplicates were found and eliminated, leaving 373 articles, from which 170 met the exclusion criteria and were removed. Full-text screening was performed for the remaining 202 articles and 65 met the eligibility criteria (Figure 1): Section 3.1 (21), Section 3.2 (13), Section 3.3 (4), Section 3.4 (14), and Section 3.5 (13). Abbreviations: GSH: glutathione; SOD: superoxide dismutase; MDA: malondialdehyde; H 2 O 2 : hydrogen peroxide; Nrf2: nuclear factor erythroid 2-related factor 2; NOX: nitrogen oxides; cAMP/PKA: cyclic adenosine monophosphate/protein kinase A; NAD: nicotinamide adenine dinucleotide; ROS: reactive oxygen species; NAA: N-acetyl aspartate; PLP: proteolipid protein; Olig 1: oligodendrocyte transcription factor 1; NGF: nerve growth factor; MMP-9: metalloproteinase 9; TNF: tumor necrosis factor; IL: interleukin; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; SIRT: sirtuin 1; VEGF-A: vascular endothelial growth factor A; VEGF-R1: vascular endothelial growth factor receptor 1; NeuN: neuronal nuclei; DXC: doublecortin; BrdU: 5-bromo-2 -deoxyuridine; PSD95: postsynaptic density protein 95; SYN: synaptophysin; VGAT: vesicular GABA transporter; VGLUT1: vesicular glutamate transporter 1; GFAP: glial fibrillary acidic protein; Otx1: orthodenticle homolog 1 [Drosophila]; Sox2: sex determining region Y [Sry]-related high mobility group box2; GSK3β: glycogen synthase kinase 3 beta; BDNF: brain-derived neurotrophic factor; DYRK1A: dual-specificity tyrosine phosphorylation regulated kinase 1A.…”

“…We further review the effect of catechins on Down syndrome (DS) and Fetal Alcohol Spectrum Disorders (FASD). DS is the most common chromosome abnormality among newborns (trisomy 21), with an estimated prevalence of 23/10,000 births [ 13 , 14 ], while FASD is caused by the toxic and teratogenic effects of prenatal alcohol consumption, with global and European prevalence of 7.7/1000 and 19.8/1000, respectively [ 15 , 16 ]. Recent evidence shows a common cellular and molecular origin disrupted by trisomy and alcohol intake, leading to craniofacial and neurocognitive phenotypes of DS and FASD [ 17 ].…”

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

“…Accumulation of damaged mitochondria is associated with oxidative stress (Bordi et al, 2019 ), and recent studies linked mitochondrial defects and oxidative stress with insulin resistance in the development of AD pathology in DS (Lanzillotta et al, 2021 ). Oxidative stress can drive protein oxidation and the formation of protein aggregates (Lanzillotta and Di Domenico, 2021 ) which are then cleared by protein quality control systems. Among the latter, the integrated stress response (ISR) downregulates protein synthesis to respond to stress.…”