Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide

Yan, Shi‐Fang; Yan, Shi Fang; Chen, X; Fu, Jin; Chen, M; Kuppusamy, Periannan; Smith, Mark A.; Perry, George; Godman, Gabriel C.; Nawroth, Peter P.

doi:10.1038/nm0795-693

Cited by 391 publications

(207 citation statements)

References 27 publications

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“…This event may ultimately result in APP gene overexpression. In this respect it should be further extended by the recent observation, made by Yan and colleagues (37), that NF-B activity is significantly augmented in AD brain compared to controls. Transfer of this knowledge to the understanding of the neuropathology of AD, although reductive, could contribute to open novel perspectives in the way we think about the disease.…”

Section: Discussionmentioning

confidence: 87%

“…We propose that NF-B/Rel proteins may represent the point of convergence of several signaling pathways relevant for initiating or accelerating those events, like inflammatory mediators, excitatory amino acids, and glycated formation (37), that ultimately contribute to the process of neuronal dysfunction and degeneration in AD. To this regard, the APP itself, whose gene expression is up-regulated in response to several stressing circumstances including head injury, neurotoxicity, and focal ischemia (38 -43) could be viewed as acute-phase protein.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

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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“…Evidence of oxidant stress, associated with neuronal injury in AD, is manifested by expression of heme oxygenase type 1, malondialdehydelysine epitopes, and nuclear localization of the p50 subunit of NF-B (16,(24)(25)(26)(27)(28)(29). Cellular oxidant stress is observed both in neurons bearing neurofibrillary tangles, and in those without tangles close to A␤ plaques, indicating a relationship between the generation of free radicals and neuropathologic events.…”

Section: Resultsmentioning

confidence: 99%

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Yan

Zhu²,

Fu³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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387

153

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In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloidbeta peptide (A␤) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for A␤, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor B-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to A␤ deposits, and in cerebrospinal fluid from AD patients there was Ϸ5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by A␤-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to A␤, consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of A␤ on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.

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“…On parallel control sections, primary antibody was replaced by blocking buffer. p50 immunohistochemistry was performed as described by Yan et al (1995). The immunohistochemistry results were evaluated independently by two investigators and, according to the staining intensity, blindly scored as negative (Ϫ), faintly positive (ϩ), and positive (ϩϩ).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Interaction of the Receptor for Advanced Glycation End Products (RAGE) with Transthyretin Triggers Nuclear Transcription Factor kB (NF-kB) Activation

Sousa¹,

Yan

Stern

et al. 2000

Laboratory Investigation

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164

122

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SUMMARY:Mutated transthyretin (TTR) fibrils are associated with the pathology of familial amyloidotic polyneuropathy (FAP), in which extracellular amyloid deposits lead to degeneration of cells and tissues, in particular neurons of the peripheral nerve. Here we present evidence that the receptor for advanced glycation end products (RAGE), previously associated with Alzheimer's disease, acts as a selective cell surface acceptor site for both soluble and fibrillar TTR. Immunohistochemical studies demonstrating increased expression of RAGE in FAP tissues suggested the relevance of this receptor to TTR-induced fibrillar pathology. In vitro studies using soluble RAGE showed saturable specific interaction with soluble and fibrillar TTR with a K d of ϳ120 nM. However, no binding was observed when soluble TTR was combined with retinol-binding protein, which represents the form in which TTR normally circulates in plasma. Specific binding of TTR to RAGE-transfected Chinese hamster ovary cells (which was completely blocked by anti-RAGE) was observed, confirming that RAGE could mediate TTR binding to cellular surfaces. RAGE-dependent activation of nuclear transcription factor kB (NF-kB) by TTR fibrils was shown in PC-12 cells stably transfected to overexpress the receptor. Furthermore, FAP nerves showed up-regulation of p50, one of the NF-kB subunits, when compared with age-matched controls. From these observations we predict that, in vivo, the presence of TTR fibrils associated with cellular surfaces of FAP patients, by contributing to NF-kB activation, leads to the pathogenesis of neurodegeneration. Further insights into the consequences of the interaction of fibrillar TTR with RAGE may therefore provide a better understanding of neurodegeneration associated with FAP. (Lab Invest 2000, 80:1101-1110.F amilial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR) fibrils in several tissues, particularly in the peripheral nervous system (Saraiva, 1995). In the peripheral nerves, amyloid infiltrates the epineurium, the perineurium, and especially the endoneurium. Extensive amyloid deposition is also observed in the meninges, in the spinal and autonomic ganglia, throughout the connective tissue, and in a perivascular distribution. In contrast, no amyloid deposition is detected in the brain. Mutated TTR is the main component of these amyloid fibrils. Several mutations in TTR have been described, the most common being a valine (Val) for methionine (Met) substitution at position 30 of the protein (Val30Met) (Saraiva et al, 1983). Nonmutated TTR also deposits as amyloid in senile amyloidosis (Gustavsson et al, 1995). TTR is a plasma homotetrameric protein of approximately 55 kDa produced early in development and highly conserved in evolution (Blake et al, 1974). TTR functions as a carrier for thyroxine (T 4 ) and retinol (vitamin A) (Raz et al, 1970) by formation of a complex with retinol-binding protein (RBP). Under physiological conditions, TTR circu...

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Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide

Cited by 391 publications

References 27 publications

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

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

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Interaction of the Receptor for Advanced Glycation End Products (RAGE) with Transthyretin Triggers Nuclear Transcription Factor kB (NF-kB) Activation

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