Global Alzheimer Research Summit

Gonsalves, Danielle; Jovanović, Katarina; Dias, Bianca Da Costa; Weiß, Stefan

doi:10.4161/pri.6.1.18854

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…Mounting evidence suggest that local inflammatory responses are mediated by astrocytes and that these astrocytes are not simply passive supportive cells, but contribute to the pathological processes of neurodegenerative diseases (Zaheer et al, 2012) and precede neuronal alterations and behavioral impairment in the progression of AD (Brambilla et al, 2012). Epidemiological studies suggest that saturated free fatty acids may increase the risk of AD (Takechi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Liu

Martin

Kohler

et al. 2013

Experimental Neurology

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Deregulation of calcium has been implicated in neurodegenerative diseases, including Alzheimer’s disease (AD). Previously, we showed that saturated free-fatty acid, palmitate, causes AD-like changes in primary cortical neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from astrocytes cultured in palmitate induces AD-like changes in neurons are unknown. This study demonstrates that this condition media from astrocytes elevates calcium level in the neurons, which subsequently increases calpain activity, a calcium-dependent protease, leading to enhance p25/Cdk5 activity and phosphorylation and activation of the STAT3 (signal transducer and activator of transcription) transcription factor. Inhibiting calpain or Cdk5 significantly reduces the upregulation in nuclear level of pSTAT3, which we found to transcriptionally regulate both BACE1 and presenilin-1, the latter is a catalytic subunit of γ-secretase. Decreasing pSTAT3 levels reduced the mRNA levels of both BACE1 and presenilin-1 to near control levels. These data demonstrate a signal pathway leading to the activation of STAT3, and the generation of the amyloid peptide. Thus, our results suggest that STAT3 is an important potential therapeutic target of AD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Liu

Martin

Kohler

et al. 2013

Experimental Neurology

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“…The neuropathological hallmarks of AD include intracellular neurofibrillary tangle formation (aggregates of hyper-phosphorylated microtubule associated protein, tau)4 and extracellular Aβ plaque deposition5. The Aβ peptide and more specifically the 42 amino acid isoform (Aβ 42 ), is largely considered the primary disease causing agent in Alzheimer's disease (as Aβ accumulation is a pre-requisite for tau hyperphosporylation, the other AD-associated feature)67.…”

mentioning

confidence: 99%

Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease

Jovanović

Gonsalves

Dias

et al. 2013

Sci Rep

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Alzheimer's disease (AD) is the most prevalent form of dementia. The amyloid beta (Aβ) peptide is the predominant candidate aetiological agent and is generated through the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta (β) and gamma (γ) secretases. Since the cellular prion protein (PrPc) has been shown to regulate Aβ shedding, we investigated whether the cellular receptor for PrPc, namely the 37 kDa/67 kDa Laminin Receptor (LRP/LR) played a role in Aβ shedding. Here we show that LRP/LR co-localises with the AD relevant proteins APP, β- and γ-secretase, respectively. Antibody blockage and shRNA knock-down of LRP/LR reduces Aβ shedding, due to impediment of β-secretase activity, rather than alteration of APP, β- and γ-secretase levels. These findings indicate that LRP/LR contributes to Aβ shedding and recommend anti-LRP/LR specific antibodies and shRNAs as novel therapeutic tools for AD treatment.

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“…Alzheimer's Disease (AD) is the predominant progressive dementing neurodegenerative disorder afflicting the elderly1 and is characterized by “positive” and “negative” lesions including amyloid beta plaques, neurofibrillary tangles and neuronal, neuropil and synaptic loss respectively23. Many of the neuronal perturbations in AD are attributable to and probably induced by the amyloid beta (Aβ) peptide2.…”

mentioning

confidence: 99%

Anti-LRP/LR specific antibody IgG1-iS18 and knock-down of LRP/LR by shRNAs rescue cells from Aβ42 induced cytotoxicity

Dias

Jovanović

Gonsalves

et al. 2013

Sci Rep

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Alzheimer's disease (AD) is characterized by neurofibrillary tangles, senile plaques and neuronal loss. Amyloid beta (Aβ) is proposed to elicit neuronal loss through cell surface receptors. As Aβ shares common binding partners with the 37 kDa/67 kDa laminin receptor (LRP/LR), we investigated whether these proteins interact and the pathological significance of this association. An LRP/LR-Αβ42 interaction was assessed by immunofluorescence microscopy and pull down assays. The cell biological effects were investigated by 3-(4,5-Dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide and Bromodeoxyuridine assays. LRP/LR and Αβ42 co-localised on the cell surface and formed immobilized complexes suggesting an interaction. Antibody blockade by IgG1-iS18 and shRNA mediated down regulation of LRP/LR significantly enhanced cell viability and proliferation in cells co-treated with Αβ42 when compared to cells incubated with Αβ42 only. Results suggest that LRP/LR is implicated in Αβ42 mediated cytotoxicity and that anti-LRP/LR specific antibodies and shRNAs may serve as potential therapeutic tools for AD.

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Global Alzheimer Research Summit

Cited by 6 publications

References 5 publications

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease

Anti-LRP/LR specific antibody IgG1-iS18 and knock-down of LRP/LR by shRNAs rescue cells from Aβ42 induced cytotoxicity

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