Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

Abstract

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.

Epigallocatechin-3-Gallate Plus Omega-3 Restores the Mitochondrial Complex I and F0F1-ATP Synthase Activities in PBMCs of Young Children with Down Syndrome: A Pilot Study of Safety and Efficacy

“…Mitochondrial estrogen receptors have been found in various tissues and cell types, including brain [ 52 ] and heart [ 53 ]. Mitochondrial dysfunctions occur during aging [ 5 ] and mitochondrial biogenesis, bioenergetics and dynamics play a central role in neurogenesis and neuroplasticity [ 1 ]. Consistently, dysfunctional mitochondria and altered redox homeostasis are involved not only in the pathogenesis of DS, but also in other neurodevelopmental disorders such as Rett syndrome, Fragile X syndrome, autism spectrum disorders, attention deficit hyperactivity disorder, for which targeting mitochondria is now considered as a therapeutic opportunity [ 54 , 55 , 56 , 57 , 58 ].…”

“…It is also known that oxidative stress (OS) and mitochondrial dysfunction play a key role in DS pathogenesis. Individuals with T21 display a pro-oxidant status [ 5 ], starting as early as the fetal period [ 6 ]. Cellular redox homeostasis is important for synaptic plasticity, neuroinflammation, vesicle-mediated transport, signal transduction, protein folding and degradation [ 7 ].…”

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“…Dyrk1 is a serine threonine kinase that has been suggested to be at the crossroads of many important 26,27 Abnormal expression and activity of Dyrk1A levels was found to occur in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and induces loss of neurons. 28,29 Meanwhile, the overexpression of DYRK1A in the brain damage after ischaemic stroke could initiate activity of apoptotic factors or stimulates the pro-apoptotic pathways ASK1/JNK under oxidative stress. 30,31 As a result of these findings, selective Dyrk1A inhibitors have emerged as an attractive drug target for a variety of diseases.…”

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome

“…In terms of oxidative stress, patients with DS show higher oxidative stress levels because of alterations of the kynurenine metabolic pathway, decreased production of antioxidants, and triplication of the SOD1, RCAN1 and APP genes ( Gomez et al, 2020 ; Perluigi et al, 2020 ). Finally, patients with DS also show (i) increased tau hyperphosphorylation because of the triplication of the ETS2 and DYRK1A genes ( Gomez et al, 2020 ; Hartley et al, 2015 ), (ii) increased neuronal apoptosis caused by the coordinated action of SOD1, DYRK1A, and ETS2 ( Martínez-Cué and Rueda, 2020 ), (iii) increased mitochondrial dysfunction linked to the triplication of the S100B and SOD1 genes ( Dierssen et al, 2020 ), and (iv) altered endocytosis and synaptic trafficking because of triplication of the RCAN1 and SYNJ1 genes ( Gomez et al, 2020 ). All of the elements mentioned above (summarized in Fig.…”