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|Year : 2021 | Volume
| Issue : 1 | Page : 32-41
Alzheimer's Disease in the Down Syndrome: An Overview of Genetics and Molecular Aspects
Fabiana de C Gomes, Marlon F Mattos, Eny M Goloni-Bertollo, Érika C Pavarino
Genetics and Molecular Biology Research Unit (UPGEM), Department of Molecular Biology, São José do Rio Preto Medical School (FAMERP), São José do Rio Preto – SP, Brazil
|Date of Submission||26-Nov-2017|
|Date of Decision||26-May-2021|
|Date of Acceptance||16-Sep-2018|
|Date of Web Publication||24-Feb-2021|
Érika C Pavarino
Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto – SP
Source of Support: None, Conflict of Interest: None
The overexpression of the amyloid precursor protein (APP) gene, encoded on chromosome 21, has been associated in Down syndrome (DS) with the development of early-onset Alzheimer's disease (EOAD). The increase in APP levels leads to an overproduction of amyloid-β (Aβ) peptide that accumulates in the brain. In response to this deposition, microglial cells are active and generate cascade events that include release cytokines and chemokine. The prolonged activation microglial cells induce neuronal loss, production of reactive oxygen species, neuron death, neuroinflammation, and consequently the development of Alzheimer's disease (AD). The intrinsically deficient immune systems in people with DS result in abnormalities in cytokine levels, which possibly contribute to the development of neurodegenerative disorders such as AD. Knowledge about the biomarkers involved in the process of neurodegeneration and neuroinflamation is important for understanding the mechanisms involved in the incidence and the precocity of AD in individuals with DS.
Keywords: Alzheimer's disease, amyloid, bioinformatics, cytokines, Down syndrome.
Key Message: In DS, some peculiarities contribute to early-onset dementia and influence the neuroinflammatory response. In addition, the development of AD in individuals with DS is complex and involves the interaction of genes localized outside and inside of chromosome 21. The use of bioinformatics tools can play a peculiar role in the identification of possible target genes involved in the development of neuropathology and neuroinflammation in AD-DS.
|How to cite this article:|
Gomes Fd, Mattos MF, Goloni-Bertollo EM, Pavarino &C. Alzheimer's Disease in the Down Syndrome: An Overview of Genetics and Molecular Aspects. Neurol India 2021;69:32-41
|How to cite this URL:|
Gomes Fd, Mattos MF, Goloni-Bertollo EM, Pavarino &C. Alzheimer's Disease in the Down Syndrome: An Overview of Genetics and Molecular Aspects. Neurol India [serial online] 2021 [cited 2021 May 7];69:32-41. Available from: https://www.neurologyindia.com/text.asp?2021/69/1/32/310062
Down syndrome (DS) or trisomy 21 (T21), is a chromosomal abnormality with complete or partial copy of human chromosome 21 (HSA21), the incidence of the number of live births varies in different countries. In addition, peculiar factors such as sociodemographic can affect the survival of individuals with DS resulting in differences in the population number among countries. The extra copies of genes on HSA21 result in gene dosage imbalances, affecting expression and regulation throughout the genome. Gene overdoses are associated with the existence of a critical region, implying several phenotypes observed in the DS.
It has been suggested since the 1970s that the region 21q22.11-21q22.2 of 3.8–6.5 Mb localized in the distal segment of the long arm of chromosome 21, called as “Down syndrome critical region” (DSCR), is crucial to the phenotypes of DS., About 30 genes localized in this “critical region” are responsible for most features observed in T21. However, Korenberg et al. suggested that there was no single region on 21q responsible for the phenotype of the syndrome, as they showed the contribution of genes outside of the DSCR. Furthermore, other studies have demonstrated that multiple critical regions or critical genes can contribute to the appearance of features associated with T21., Contrarily, Chabert et al.'s Galois lattice analysis associated only the region between the D21S17 and ETS proto-oncogene 2, transcription factor (ETS2) sequences, which lie in the proximal part of 21q22.3, with the pathogenesis of the DS., More recently, Pelleri et al. identified a smaller region on 21q22.13 as critical to the manifestation of typical features in the DS. Therefore, there is still no consensus about the region that is determinant for clinical manifestations.
Although several studies have been performed to identify a “critical region” that contributes to clinical manifestations, the main point is to understand the direct or indirect effects of dosage-sensitive genes on the phenotype of the syndrome and the consequences of interactions between specific genes or subsets of genes on clinical manifestations., The genic interaction and overproduction result in deregulation of biochemical pathways that are implicated in clinical aspects and posterior complications.,
Clinical aspects of DS are complex and variable. Although some characteristic are observed in all individuals, others are seen in only some persons. Similarly, all individuals are characterized by a set of facial and physical features, such as muscle hypotonia, flat-looking face, cognitive impairment, and immune system defects., In DS, the brain is morphologically and anatomically characterized by diminished volumes of hippocampus and of the temporal and frontal lobes., Postmortem brain of DS has showed abnormal distributions of neurons in some brain regions, decreased neurogenesis, neuronal hypocellularity, and hypoplasia, resulting in reduction in the number of neurons and synaptic transmission.,,, In most cases, additional problems exist, such as hearing and visual defects, respiratory disorders, gastrointestinal tract anomalies, congenital heart disease, and susceptibility for developing early-onset Alzheimer's disease (AD).,, It is likely that genic imbalance observed in DS contributes to development of neurodegenerative factors such as AD.,,
| » Alzheimer's Disease and the Neuropathology in Down Syndrome|| |
AD is a chronic neurodegenerative disease characterized by loss of memory and other cognitive abilities. It is also a main cause of dementia worldwide with an incidence of 100 person-years., The risk of AD increases progressively in advancing age; about 25%–45% of people more than 85 years of age have dementia. Based on the ages of the onset of dementia, AD is divided into two subtypes: early-onset AD (EOAD), which affects persons between 30 and 60 years old, and late-onset AD (LOAD), which is more frequent in persons older than 60 years. Clinical symptoms of EOAD and LOAD are similar, including decline in memory and impairment of the cognitive functions, language, and motor skills. Over time, the severity of these symptoms increases, leading to difficulties performing physical and cognitive functions in work, home, and social situations.
Several investigators have reported EOAD in adults with DS.,,,, Usually, AD appears two to three decades earlier in people with DS than in people without T21. Recently, the average age for diagnosis and dementia incidence in DS was reported to be around 47 years. After 60 years, the incidence of neuropathology decreases, likely due to variations in diagnoses and/or the absence of information about mortality rates associated with dementia.
Aberrant dosages of genes and noncoding sequences present on HSA21 may have a role in the development of AD in individuals with DS (DS-DA). In HSA21, specifically in the region 21q22.11-21q22.2, there are genes that contribute to many neurological features of DS; on the other hand, some findings have focused on the region 21q21–21q22.3, which contains genes important for brain development.,
In this review, we performed a search in PubMed (data collected until the year 2017) and identified 464 genes localized in the region 21q22.11-21q22.3, reported as a critical region for most neurological phenotypes of DS. We analyzed the genes through Database for Annotation Visualization and Integrated Discovery (DAVID) version 6.8. Further analyses excluded 23 genes due to information obtained from the Gene Entrez database. After exclusion, 441 genes were subjected to multiple tests. We selected only significant results (P < 0.05) related to neurologic functions.
When analyzing disease classes, we observed that 25 genes showed moderate concordance (κ = 0.44, P = 0.006, multiple tests of DAVID) with neurological diseases and other systemic dysfunctions. We also verified that 55 genes were involved in neurological and metabolic dysfunctions; however, the concordance level was not significant (κ = 0.40, P = 0.096, multiple tests of DAVID). Finally, the analyses that considered only neurological dysfunctions showed that 19 genes [Table 1] were involved in this function. These genes were selected for functional annotation of the gene ontology [Table 2]. Of these 19 genes, only 21% [superoxide dismutase 1 (SOD1), runt-related transcription factor 1 (RUNX1), dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), and lipid transporter ATP-binding cassette G1 (ABCG1)] have been described to be involved in AD-DS. Therefore, the role of many genes that have been presented in this bioinformatics analysis remains unknown. The knowledge about these genes may direct future research on potential targets involved in dementia.
|Table 1: Gene ID, symbol, description, and location of genes in the critical region of the HSA21 involved in neurological disease|
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|Table 2: Functional annotation of the genes involved in neurological dysfunctions|
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Independent of the localization of triplicate genes in HSA21, particularly for neurological phenotypes, imbalances and changes in the expression of genes located within or even outside of the DRSC affect mechanisms involved in the development of tissue and cellular differentiation, leading to neuronal reductions that favor the emergence of neurological complications, such as EOAD.
| » Neuropathologic Mechanisms Linked to AD in DS|| |
Clinical, histopathological, and molecular aspects of AD are observed in adults with DS., Studies have reported that individuals with DS at age 30 years show severe cognitive deterioration, such as difficulties with verbalizing, apraxia, and other dysfunctions similar to dementia that can be linked to frontal lobe dysfunctions. Current findings support the unclear association between severity of cognitive disability and development of AD in DS (AD-DS), possibly because the preexisting cognitive impairments in DS make a neuropathological diagnosis of AD difficult. After 40 years of age, the neuropathology rapidly increases and AD may be diagnosed. The main genetic factors involved in clinical manifestations of AD-DS are shown in [Figure 1].
|Figure 1: Schematic of genetic factors involved in clinical manifestations of AD-DS in which are described the events of pathogenesis DS-AD (light gray box) and the interaction of genes inside (medium-dark gray box) and outside (dark gray box) of chromosome 21 with the neurologic phenotypes and clinical aspects (white box): human chromosome 21 (HSA21); Down syndrome (DS); beta amyloid protein (Aβ); amyloid precursor protein (APP); apolipoprotein E (APOE); lipid transporter ATP-binding cassette G1 (ABCG1); beta-secretase 1 (BACE1) beta-secretase 2 (BACE2); microRNA 155 (Mir-155); ETS proto-oncogene 2, transcription factor (ETS2); Presenilin 1 (PSEN 1); Presenilin 2 (PSEN 2); dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A); small ubiquitin-related modifier 3 (SUMO3); cystatin C (CST3); coxsackie virus and adenovirus receptor (CXADR); regulator of regulate calcineurin 1 (RCAN1); microtubule affinity-regulating kinase 4 (MARK4); ADAM metalloproteinase with thrombospondin type 1 motif, 1 (ADAMTS1); ADAM metalloproteinase with thrombospondin type 1 motif, 5 (ADAMTS5); S100 calcium binding protein astrocyte-derived (S100B); superoxide-dismutase type 1 (SOD-1); runt-related transcription factor 1 (RUNX1) genes|
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The copy extra of amyloid precursor protein (APP) gene, located on chromosome 21, may have a key role in development of neuropathology in DS. The overexpression of APP in DS results in an increase in amyloid-β (Aβ) peptides associated with dementia. Histological analyses of brain tissue of individuals with DS without AD (DS-non AD) have demonstrated that Aβ can accumulate, overtime, before the EOAD. This deposition occurs in the intracellular (neuron) and extracellular (around the blood vessel and neurons) spaces, forming neuritic plaques and neurofibrillary tangles (NFTs).,,
Neuritic plaques, also called senile, dendritic, or amyloid plaques, refer to abundant depositions of insoluble Aβ in brain parenchyma. The accumulation of Aβ initially forms oligomers that slowly aggregate in the form of fibrils and senile plaques. Amyloid fibrils are formed by soluble proteins that agglomerate to form insoluble aggregates that are not easily degraded. This aggregation generates neurotoxicity and influences kinase/phosphatase activity, inducing tau protein hyperphosphorylation and causing the formation of NFTs, consequently affecting the synaptic and neuronal functions, causing neuronal death and the eventual appearance of AD.,
NFTs are intraneuronal aggregations of hyperphosphorylated forms of the microtubule-associated protein tau. The Tau protein present in axon plays a role in stabilization of microtubules in neurons. Abnormal accumulation and aggregation of the tau filaments (hyperphosphorylated form) in cell bodies and dendrites induce neurotoxicity and have been implicated in AD pathophysiology.,
Studies have demonstrated the participation of Tau in the development of neuropathology in the DS.,,, Some genes localized in chromosome 21 such as the regulator of regulate calcineurin 1 (RCAN1) and Dyrk1A contribute to dysregulation of tau phosphorylation, resulting in hyperphosphorylation in the adult DS brain. Although tau has been associated with the development of EOAD in individuals with DS, amyloid cascade hypothesis, due to APP triplication, is still the primary proposal for the cause of dementia in people with DS.,
The overexpression of APP is four to five times greater in individuals with DS. In normal conditions, APP protein is not neurotoxic; however, errors in processing APP lead to the production and accumulation of Aβ. The APP can be cleaved by three different enzymes: α, β, and γ-secretase. The α enzymes compete with the β enzymes for cleavage of APP. This competition drives APP processing through amyloidogenic and non-amyloidogenic pathways.
In the non-amyloidogenic pathway, the α-secretase enzyme cleaves APP, generating fragments of amyloid precursor-protein-α (sAPPα) which have neuroprotective functions. In the amyloidogenic pathway, the cleavage of APP is mediated by β-secretase (BACE1 and BACE2) enzymes, producing APP-β (sAPPβ). Later, γ-secretase enzyme cleaves sAPPα, producing shorter P3 fragments (Aβ17-x), whose biological roles are unknown and also cleave sAPPβ that produce Aβ peptides., In pathological conditions, errors in APP cleavage processing and/or imbalances between Aβ generation and clearance result in excess of long Aβ peptides (Aβ40/42) that can aggregate into amyloid plaques, giving rise to AD neuropathologies., In individuals with DS more than 40 years old, are observed reductions in α-secretase and increases in β-secretase. These results suggest that alterations of secretase activity may be associated with production of amyloidogenic fragments and accumulation of Aβ.
The causes of modifications in the steps of APP cleaving and dysregulation between the production and degradation of Aβ may be explained by dominant autosomal mutations or genetic polymorphisms, including APP, Presenilin 1 and 2 (PSEN 1/2 or PS1/2), ABCG1, and apolipoprotein E (APOE) genes., PSEN 1/2 proteins are components of the γ-secretase complex that regulate APP processing in normal conditions, and mutations of PSEN 1/2 genes can induce high production of long Aβ peptides (Aβ-40/42); these peptides are known as the main pathogenic form of Aβ, associated with occurrence of EOAD and severe forms of AD.,,,, In addition, in DS it was suggested that Dyrk1A phosphorylates the PSEN1 contributing to high γ-secretase activity, and consequently elevated amounts of Aβ40/42 in the brain.,
Regarding APOE in the brain, this protein participates in neuronal signaling, regulation of the cholinergic neurotransmitter system, and Aβ clearance. Although it is considered a biomarker of late-stage AD, studies have showed an association between APOE gene, particularly alleles μ4 (apoE4), and the development of dementia in adults with DS. Still, the gene ABCG1 is involved in the regulation of cholesterol and influences the processing of APP and clearance of Aβ.
Others proteins such as BACE2 and small ubiquitin-related modifier 3 (SUMO3) are also encoded in HSA21, modifying APP post-translationally, which may change Aβ production. Moreover, additional factors such as microRNA-155 and ETS2 transcription factor located in HSA21 have been reported as modulating/processing APP. The acting pathways of microRNA-155 and ETS2 in APP processing are different, but both may induce Aβ generation., The RUNX1, also located in HSA21, was associated with AD in people with DS. RUNX1 is important in transcriptional regulator neural progenitor cell and has been implicated in the development of neuronal phenotypes observed in individuals with DS.
For non-chromosome 21 genes, single-nucleotide polymorphisms in cystatin C (CST3) and microtubule affinity-regulating kinase 4 (MARK4) genes were related with risks of dementia in adults with DS. The CST3 code inhibitory protein CysC binds with Aβ, inhibiting aggregation and preventing the formation of fibrils. The MARK4 encodes proteins that phosphoryl microtubule-associated protein. Errors in expressions of MARK4 are related to increases in phosphorylation of tau and may lead to development of EOAD. Thus, the interaction of genes localized outside and inside of chromosome 21 may favor aggregation of Aβ and may lead to neuroinflammation linked to DS-AD pathogenesis.,,
| » Some Aspects of Inflammation Associated with AD in DS|| |
In DS, some peculiarities influence neuroinflammatory response. The exacerbation of amyloid deposition in DS favors a neuronal loss and consequently occurrence of EOAD. Aβ accumulates in a brain's active microglial cells; these cells interact with amyloid plaques, resulting in an event known as an “activated” macrophage phenotype (M1), inducing a proinflammatory cascade and resulting in the production of chemokines and cytokines involved in Aβ clearance and preventing neuronal death. However, microglial-prolonged activation and increase in proinflammatory factors favor the production of reactive oxygen species, propitiating oxidative stress, neurotoxicity, and neuron death, causing neuroinflammation.
In parallel, an alternative activated macrophage phenotype (M2) is responsible for tissue reparation through the release of anti-inflammatory cytokines and reduction in proinflammatory cytokine concentrations. The release or inhibition of inflammatory mediators depends on the balance between “classical” (M1) and “alternative” (M2) activations; consequently, dysregulation of pro- and anti-inflammatory molecules favors AD and DS neuropathology.,
Genes involved in the inflammatory response, located chromosome 21, associated with M1 phenotype also participate in the development of neuropathological manifestations in people with DS. These genes act in the upregulation of glial activation. More recently, it has been observed that an increase in marker M2 phenotypes (CD64 and CD86) in people with DS-AD had not been described in sporadic AD, suggesting a unique inflammatory phenotype in people with DS.
In DS, the intrinsically deficient immune system results in abnormalities of cytokine levels that possibly contribute to the development of neurodegenerative factors such as AD.,, [Table 3] shows that some studies (data collected until the year 2017) have reported associations of cytokine changes in DS with or without AD.,,,,,,,,,,,,,,,,,,,,,, These findings indicate a possible accentuated inflammatory response before appearance of neuropathology.,,,,,,,,,,,,,,,,,,,
The triplicated genes in T21 accentuate the inflammatory response inducing high expressions and release of several pro-inflammatory cytokines, such as IL-1β., Overexpression, upregulation, or liberation of IL-1β induces an increase in APP, contributing to Aβ deposition and activation of pathways involved in the formation of senile plaques and NFTs.
Others genes involved in the inflammatory process, also located in HSA21, involved in the formation of senile plaques and/or NFT include S100 calcium binding protein astrocyte-derived (S100B) and SOD1 genes that participle in events related to oxidative stress; ADAM metalloproteinase with thrombospondin type 1 motif, 1 (ADAMTS1), ADAM metalloproteinase with thrombospondin type 1 motif, 5 (ADAMTS5), and Coxsackie virus and adenovirus receptor (CXADR) genes which active pathways such as mitogen-activated protein kinase (MAPK)-p38.
The inflammatory markers in the blood, brain, and cerebrospinal fluid may indicate signs of dementia and contribute to diagnoses of AD in persons with DS ,,,; however, investigations of markers for early diagnosis are necessary. The identification of target biomarkers is crucial for drug development and of new therapeutic methods that may conduce a treatment of EOAD in adults with DS.
| » Summary|| |
In DS, some peculiarities contribute to early-onset dementia and influence the neuroinflammatory response. In addition, the development of AD in individuals with DS is complex and involves the interaction of genes localized outside and inside of chromosome 21. Still, according to bioinformatics analysis of this review, some genes on chromosome 21 associated with neurological disorders has not been investigated or understood in the context of AD and DS. Therefore, future research involving bioinformatics analysis may help to map the interaction of genes on chromosome 21 with genes located on other chromosomes that may have a peculiar role in the development of the neuropathology and neuroinflammation in the AD-DS.
The authors would like to thank National Council for Scientific and Technological Development (CNPq) - Finnance Code 310806/2018-6 and São Paulo Research Foundation 2018/09126-0 and 2018/24825-2 and Prof. Dr. João Simão de Melo Neto of Urogenital System Clinical and Experimental Research Unit (UPCEURG) of Federal University of Pará (UFPA) for technical support in bioinformatics analysis.
Financial support and sponsorship
“This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil. Finnance Code 001”.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]