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Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis.

Wilcock DM, Griffin WS - J Neuroinflammation (2013)

Bottom Line: In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD).The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines.The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.

ABSTRACT
Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.

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Schematic highlighting the importance of inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21. Chromosome 21 genes triplicated in trisomy 21 activate microglia with overexpression and release of proinflammatory cytokines, especially IL-1β, which, in turn, induces further increases in precursor protein for β-amyloid (APP), favoring β-amyloid (Aβ) plaque deposition, and in mitogen-activated protein kinase (MAPK)-p38-dependent phosphorylation and production of phosphorylated tau, favoring neurofibrillary tangle formation, and through nuclear factor κB (NFκB) activity such changes sustain neuroinflammatory responses and consequent neuropathological change.
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Figure 1: Schematic highlighting the importance of inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21. Chromosome 21 genes triplicated in trisomy 21 activate microglia with overexpression and release of proinflammatory cytokines, especially IL-1β, which, in turn, induces further increases in precursor protein for β-amyloid (APP), favoring β-amyloid (Aβ) plaque deposition, and in mitogen-activated protein kinase (MAPK)-p38-dependent phosphorylation and production of phosphorylated tau, favoring neurofibrillary tangle formation, and through nuclear factor κB (NFκB) activity such changes sustain neuroinflammatory responses and consequent neuropathological change.

Mentions: The principal conclusion one may draw from information presented here regarding the influence of triplication of chromosome 21 genes on neuropathogenesis and development of the clinical and neuropathological manifestations of AD and AD in DS is that many chromosome 21 genes upregulate classical neural immune responses of activated microglia, which are now classified according to systemic immune macrophage profiles as either classical M1 responses that favor overexpression of pro-inflammatory cytokines, or alternative M2 responses that favor overexpression of anti-inflammatory cytokines. As so many chromosome 21 genes are primarily associated with M1, that is, proinflammatory responses, we propose that M1 is the principle glial activation state that will be observed in the DS brain. This is commonsensical as, for example in experimental conditions, triplication of the major IFN receptor genes IFNAR1, IFNAR2 and IFNGR2 is associated with enhancement of interferon signaling and TIAM1, SOD1, and PRMT2 are associated with increases in oxidative stresses, and S100B induces expression of APP as well as IL-1α and β. Moreover, in brains of fetuses, neonates, children, and adults with DS, astrocytes are activated and express excess levels of S100B adjacent to activated microglia overexpressing IL-1α and neurons overexpressing APP. These findings, together with triplication of the βAPP gene in DS and experimental evidence of neuronal stress-induced increases in βAPP expression and parallel secretion of sAPP for resultant activation of microglia, evidenced by increases in oxidative markers and overexpression and release of IL-1β, suggest that triplication of chromosome 21 genes, perhaps especially βAPP, may account for most of the very early neuroinflammatory and oxidative changes in DS. By analogy, the neuronal stress triggered by the many risk factors that favor development of AD, manifested as neuronal overexpression of APP and release of sAPP, may be prime in inducing the dramatic neuroinflammatory responses that then result in a self-amplifying cycle (Figure 1) of increasing neuropathological changes, including neuronal stress, neuroinflammation, and synthesis of the precursors giving rise to formation of the Aβ plaques and neurofibrillary tangles diagnostic of AD.


Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis.

Wilcock DM, Griffin WS - J Neuroinflammation (2013)

Schematic highlighting the importance of inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21. Chromosome 21 genes triplicated in trisomy 21 activate microglia with overexpression and release of proinflammatory cytokines, especially IL-1β, which, in turn, induces further increases in precursor protein for β-amyloid (APP), favoring β-amyloid (Aβ) plaque deposition, and in mitogen-activated protein kinase (MAPK)-p38-dependent phosphorylation and production of phosphorylated tau, favoring neurofibrillary tangle formation, and through nuclear factor κB (NFκB) activity such changes sustain neuroinflammatory responses and consequent neuropathological change.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750399&req=5

Figure 1: Schematic highlighting the importance of inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21. Chromosome 21 genes triplicated in trisomy 21 activate microglia with overexpression and release of proinflammatory cytokines, especially IL-1β, which, in turn, induces further increases in precursor protein for β-amyloid (APP), favoring β-amyloid (Aβ) plaque deposition, and in mitogen-activated protein kinase (MAPK)-p38-dependent phosphorylation and production of phosphorylated tau, favoring neurofibrillary tangle formation, and through nuclear factor κB (NFκB) activity such changes sustain neuroinflammatory responses and consequent neuropathological change.
Mentions: The principal conclusion one may draw from information presented here regarding the influence of triplication of chromosome 21 genes on neuropathogenesis and development of the clinical and neuropathological manifestations of AD and AD in DS is that many chromosome 21 genes upregulate classical neural immune responses of activated microglia, which are now classified according to systemic immune macrophage profiles as either classical M1 responses that favor overexpression of pro-inflammatory cytokines, or alternative M2 responses that favor overexpression of anti-inflammatory cytokines. As so many chromosome 21 genes are primarily associated with M1, that is, proinflammatory responses, we propose that M1 is the principle glial activation state that will be observed in the DS brain. This is commonsensical as, for example in experimental conditions, triplication of the major IFN receptor genes IFNAR1, IFNAR2 and IFNGR2 is associated with enhancement of interferon signaling and TIAM1, SOD1, and PRMT2 are associated with increases in oxidative stresses, and S100B induces expression of APP as well as IL-1α and β. Moreover, in brains of fetuses, neonates, children, and adults with DS, astrocytes are activated and express excess levels of S100B adjacent to activated microglia overexpressing IL-1α and neurons overexpressing APP. These findings, together with triplication of the βAPP gene in DS and experimental evidence of neuronal stress-induced increases in βAPP expression and parallel secretion of sAPP for resultant activation of microglia, evidenced by increases in oxidative markers and overexpression and release of IL-1β, suggest that triplication of chromosome 21 genes, perhaps especially βAPP, may account for most of the very early neuroinflammatory and oxidative changes in DS. By analogy, the neuronal stress triggered by the many risk factors that favor development of AD, manifested as neuronal overexpression of APP and release of sAPP, may be prime in inducing the dramatic neuroinflammatory responses that then result in a self-amplifying cycle (Figure 1) of increasing neuropathological changes, including neuronal stress, neuroinflammation, and synthesis of the precursors giving rise to formation of the Aβ plaques and neurofibrillary tangles diagnostic of AD.

Bottom Line: In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD).The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines.The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.

ABSTRACT
Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.

Show MeSH
Related in: MedlinePlus