LPYFDa Neutralizes Amyloid-β-Induced Memory Impairment and Toxicity

Granic, Ivica; Masman, Marcelo F.; Mulder, Cornelis Kees; Nijholt, Ingrid M.; Naudé, Pieter; Haan, Ammerins de; Borbély, Emöke; Penke, Botond; Luiten, P.G.M.; Eisel, Ulrich

doi:10.3233/jad-2010-1297

Cited by 31 publications

(14 citation statements)

References 73 publications

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“…Future studies that inject Abeta right after fear conditioning might be able to distinguish between Abeta effects on learning and consolidation. Either way, our data are in line with previous studies that have reported effects of Abeta oligomers on learning and consolidation [13], [25], [26].…”

Section: Discussionsupporting

confidence: 93%

“…Our finding that natural Abeta oligomers acutely impair the formation of a contextual fear memory is in agreement with previous studies that injected synthetic Abeta oligomers into the ventricle or hippocampus [25], [26]. In contrast, another study that injected synthetic Abeta oligomers into the hippocampus reported an improvement of contextual fear memory, suggesting that low levels of synthetic Abeta oligomers might have beneficial effects on memory [30].…”

Section: Discussionsupporting

confidence: 92%

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Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

et al. 2012

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Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

et al. 2012

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“…Amyloids are highly sequence specific, and form stacked β-sheets of identical sequences in many molecules of the same protein [22], [23]. Therefore, amyloid formation is highly sensitive to addition of amyloid-forming or amyloid-interfering peptides with sequences identical to or slightly changed from the amyloid-forming region of the protein [48], [49]. An amyloid-forming peptide rescued the S. cerevisiae cells expressing Als5p V326N , as well as increasing surface amyloid levels in cells expressing Als5p WT and in C. albicans (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

A Role for Amyloid in Cell Aggregation and Biofilm Formation

et al. 2011

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Cell adhesion molecules in Saccharomyces cerevisiae and Candida albicans contain amyloid-forming sequences that are highly conserved. We have now used site-specific mutagenesis and specific peptide perturbants to explore amyloid-dependent activity in the Candida albicans adhesin Als5p. A V326N substitution in the amyloid-forming region conserved secondary structure and ligand binding, but abrogated formation of amyloid fibrils in soluble Als5p and reduced cell surface thioflavin T fluorescence. When displayed on the cell surface, Als5p with this substitution prevented formation of adhesion nanodomains and formation of large cellular aggregates and model biofilms. In addition, amyloid nanodomains were regulated by exogenous peptides. An amyloid-forming homologous peptide rescued aggregation and biofilm activity of Als5pV326N cells, and V326N substitution peptide inhibited aggregation and biofilm activity in Als5pWT cells. Therefore, specific site mutation, inhibition by anti-amyloid peturbants, and sequence-specificity of pro-amyloid and anti-amyloid peptides showed that amyloid formation is essential for nanodomain formation and activation.

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“…Linear amplification of RNA was performed (Amino Allyl MessageAmp II aRNA Amplification Kit; Ambion, Austin, TX) before labeling with Cy3 and Cy5 fluorescent dyes (GE Healthcare) and microarray hybridization to oligonucleotide arrays consisting of the Qiagen mouse MV3 oligo set with oligonucleotide length generally ∼70 nucleotides. General methods for data extraction, normalization, and filtration for quality and dye bias have been summarized in detail previously (21). Here data from three microarrays were analyzed in the National Cancer Institute mAdb microarray databasing system (http://madb.nci.nih.gov/) after standard Loess correction with an allowed quality ratio of 0.3.…”

Section: Oligo Microarray Hybridization and Data Analysismentioning

confidence: 99%

Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease

et al. 2012

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Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

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LPYFDa Neutralizes Amyloid-β-Induced Memory Impairment and Toxicity

Cited by 31 publications

References 73 publications

Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

A Role for Amyloid in Cell Aggregation and Biofilm Formation

Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease

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