β-Amyloid Peptide at Sublethal Concentrations Downregulates Brain-Derived Neurotrophic Factor Functions in Cultured Cortical Neurons

Tong, Liqi; Balázs, R.; Thornton, Phillip L.; Cotman, Carl W.

doi:10.1523/jneurosci.5463-03.2004

Cited by 206 publications

(160 citation statements)

References 62 publications

(96 reference statements)

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“…Moreover, in rat cortical neuron cultures, at sublethal concentrations A␤ interferes with BDNF signaling, thus increasing neuron vulnerability and abrogating BDNF protection against apoptosis induced by DNA damage or by trophic deprivation. 50 In vivo, A␤ and A␤ [25][26][27][28][29][30][31][32][33][34][35] infusion also triggered BDNF mRNA expression 7 days after the start of peptide infusion. 51 In the present study, spatiotemporal examination of the influence of A␤ [25][26][27][28][29][30][31][32][33][34][35] on BDNF protein expression revealed a sustained BDNF increase in the hippocampus and hypothalamus over time from weeks 1 to 3.…”

Section: Discussionmentioning

confidence: 99%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

116

129

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Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid ␤ protein (A␤) formed by pathological processing of the A␤ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated A␤ fragment 25-35 (A␤ 25-35 ) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled A␤ 25-35 peptide was used as negative control. The aggregated forms of A␤ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of A␤ 25-35 decreased body weight, induced short-and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, A␤ 25-35 , the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. Alzheimer's disease (AD) is a chronic neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss in brain areas responsible for learning and memory impairments. 1 The major component of senile plaques is an amyloid ␤ protein (A␤) derived from amyloid precursor protein (APP). Genetic, cell biological, and postmortem studies on AD brain, together with A␤ neurotoxicity findings, gave rise to the amyloid cascade hypothesis to explain A␤-associated neurodegenerative processes. 2 In normal healthy individuals, A␤ peptides are present only in small quantities, as soluble monomers that circulate in cerebrospinal fluid and blood. In AD patients, A␤ peptides, which vary in length from 40 to 43 amino acids, accumulate as insoluble fibrillar deposits. 3 When cultured rat hippocampal neurons are exposed to aggregated A␤ peptides, their neurites adopt a dystrophic appearance and become comparable to those observed surrounding and infiltrating senile plaques. This observation suggested that A␤ is responsible for the neuritic abnormalities in AD pathology. 4 Structure-activity studies revealed that peptides containing the highly hydrophobic 25-35 region formed stable aggregates and mediated neuronal death by necrosis or apoptosis. 5,6,7 The truncated A␤ 25-35 fragment includes extracellular and intramembrane residues that have been reported to represent an active region of A␤. 8

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Section: Discussionmentioning

confidence: 99%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

116

129

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“…31,95,[97][98][99][100] In addition, APPswe/PS1dE9 amyloid plaque producing mice show reduced SST levels in the cortex, 101 and this is likely mediated through the interference of amyloid-beta (Ab) with the BDNF-induced activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. 102 In contrast, it appears that inducing increased expression of SST may be beneficial for patients suffering from AD: compounds increasing SST expression are in phase II clinical trials as cognition enhancing agents (FK962, Astellas Pharma, Tokyo, Japan), 103 and transgenic models of amyloid deposition are reversed by environmental enrichment, 25 which is known to induce SST-NPY expression via a BDNF-dependent pathway. Thus, while altered BDNF expression may not represent the primary disturbance in AD, changed expression of, or altered responsiveness to BDNF (and subsequently decreased SST levels) may represent a critical feature of Alzheimer's disease progression.…”

Section: Discussionmentioning

confidence: 99%

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

et al. 2006

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“…The transcription promoting activity of CREB involves phosphorylation at the Ser-133 residue [46], and BDNF exposure is known to lead to the phosphorylation of this residue [e.g. 67,70]. Exposure of cortical neurons to BDNF induced a great increase in the Ser-133-phosphorylated CREB content.…”

Section: Il-1β Interferes With Bdnf-induced Activation Of the Transcrmentioning

confidence: 99%

“…Further studies should address the question of the mechanism of ceramide-induced attenuation of IRS and Shc activation by neurotrophins. It is known that ceramides activate stress activated protein kinases through different routes including pathways, which involve either PKCζ [5] Previously we demonstrated that BDNF signal transduction and neuronal survival are also suppressed in the presence of the β-amyloid peptide (Aβ 1-42 ) [70]. Like IL-1β, Aβ impaired BDNF activation of the PI3-K/Akt and Ras/MAPK pathways and suppressed the activation of transcription factors, such as CREB and Elk-1, and transcription mediated by these factors.…”

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confidence: 99%

“…The ensuing Tyr phosphorylation of these docking proteins provides binding sites for the regulatory subunit of PI3-K and the Grb/SOS complex, the activation of which propagates the signaling cascade. Our observations are consistent with the view that IL-1β interference with BDNF signaling might involve the docking proteins mediating the activation of the Ras/MAPK and PI3-K pathways.It has been observed previously that the docking step is critically involved in the inhibition by Aβ 1-42 of BDNF signaling [70] and in the downregulation by proinflammatory cytokines of insulin-and IGF-1-induced signaling in various cell types including neurons [71,81]. We examined, therefore, the effect of IL-1β on Tyr phosphorylation of the adaptor proteins linking the activated receptor with the downstream lipid and protein kinase cascades.…”

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confidence: 99%

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Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

183

136

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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

show abstract

β-Amyloid Peptide at Sublethal Concentrations Downregulates Brain-Derived Neurotrophic Factor Functions in Cultured Cortical Neurons

Cited by 206 publications

References 62 publications

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

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