Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease.

Griffin, W. Sue T.; Stanley, Laura; Chen, Ling; White, Lon R.; MacLeod, Veronica; Perrot, Linda J.; White, Charles L.; Araoz, C.

doi:10.1073/pnas.86.19.7611

Cited by 1,548 publications

(952 citation statements)

References 34 publications

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“…Thus, downstream events that may be directly or indirectly related to Aβ or tangle formation may lead to neuronal dysfunction and cognitive decline. For example, synaptic dysfunction may be a consequence of APP overexpression or increased Aβ [58,60], or other pathological molecular cascades may be engaged in DS that are associated with AD pathology such as neuroinflammation [18,19,21,59], endosomal dysfunction [6,7] and oxidative damage [45,46]. When these temporal events are considered together, DS involves the co-occurrence of features of aging and of AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

110

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Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alphasecretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

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Section: Discussionmentioning

confidence: 99%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

110

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“…Generalized astrogliosis, manifested by cellular hypertrophy and by an increase in expression of GFAP and astroglial S100B protein, was routinely observed in postmortem tissues from AD patients. 148,[151][152][153][154][155][156] More detailed analysis of astrogliosis in the brains obtained from old patients (with and without confirmed AD) have demonstrated a correlation between the degree of astrogliosis and cognitive decline; however, the same analysis failed to reveal a direct correlation between astrogliotic changes and senile plaques. 157 The morphological data showed reactive astrocytes associated with some, but not with all A␤ plaques; astrogliotic fields were also found in areas without A␤ depositions in both AD and non-AD brains.…”

Section: Morphology and Numbersmentioning

confidence: 99%

Astrocytes in Alzheimer's Disease

et al. 2010

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Summary:The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.

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“…In fact IL-1 is induced in the central nervous system following a variety of insults (23). Moreover, the cytokine is dramatically overexpressed in brains of individuals with AD and Down's syndrome (24) and it induces an increase in APP transcript levels in endothelial (11) and neuronal cells (25). On the other hand, the role of glutamate as a mediator of acute neurodegenerative events is well recognized (26).…”

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confidence: 99%

Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

Grilli

Goffi

Memo

et al. 1996

Journal of Biological Chemistry

143

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We originally reported that members of the family of transcription factors NF-B/Rel can specifically recognize two identical sequences, referred to as APP B sites, which are present in the 5 -regulatory region of the APP gene. Here we show that the APP B sites interact specifically with a complex which contains one of the subunits of the family, defined as p50 protein, and that they act as positive modulators of gene transcription in cells of neural origin. Additionally, the nuclear complex specifically binding to the APP B sites is constitutively expressed in primary neurons from rat cerebellum and it is up-regulated in response to both the inflammatory cytokine interleukin-1␤ (IL-1␤) and the excitatory amino acid glutamate. Since IL-1, whose levels are known to be induced in brain of individuals affected by Alzheimer's disease, and glutamate, are stimuli which have been regarded as major actors on the stage of neurodegenerative processes, we believe our evidence as potentially relevant for understanding the neuropathology associated with Alzheimer's disease.Alzheimer's disease (AD) 1 is a neurodegenerative disorder characterized by abnormal deposition of extracellular congophilic plaques in the brain. The main constituent of plaques is a 39-to 43-amino acid peptide, named ␤-amyloid, which is a proteolytic fragment of the amyloid precursor protein (APP) (1). In recent years, most experimental studies have been aimed at understanding the mechanisms of ␤-amyloid formation and deposition and at identifying potential risk factors which may favor these processes. In particular, APP gene mutations occurring in families with Familial AD have been correlated with disturbance in protein processing, which in turn, may predispose to ␤ amyloid formation (2, 3). However, since APP gene mutations represent a minor percentage of AD cases, it is evident that other mechanisms may exist to account for ␤-amyloid deposition. In this regard, it should not be underestimated that overexpression of the APP gene may be involved in the pathogenetic mechanisms of amyloid formation, at least in some clinical forms of the disease. Several observations underscore the potential contribution of the APP gene overexpression to favoring AD neuropathology: (i) the marked accumulation of ␤-amyloid which correlates with increased levels of APP mRNA in trisomy 21 (Down's syndrome) (4); (ii) the increased levels of APP gene transcripts in specific areas of the AD brains (5-7); (iii) the increased APP mRNA transcription in cultured fibroblasts from the Familial Alzheimer's disease-1 family (8). In addition, post-mitotic neurons which overexpress full-length APP were shown to degenerate and accumulate large amounts of amyloidogenic C-terminal fragments (9). The promoter region of the APP gene (10) has been shown to contain binding sequences for several known transcription factors (11)(12)(13)(14)(15)(16)(17)(18)(19). We reported recently (20) that a novel regulatory pathway for APP gene control at the transcriptional level may involve members of the NF...

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Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease.

Cited by 1,548 publications

References 34 publications

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Astrocytes in Alzheimer's Disease

Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

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