The secreted Alzheimer-related amyloid precursor protein fragment has an essential role in<i>C. elegans</i>

Ewald, Collin Y.; Li, Chris

doi:10.4161/pri.22310

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…The effect of the sAPL-1 fragment could be mediated by competition with insulin-like peptides (ILPs) for binding to the insulin/IGF-1 receptor (DAF-2). Alternatively, it could be acting on a receptor protein tyrosine phosphatase (RPTP) able to modify downstream signaling of the insulin/IGF-1 receptor [ 16 , 86 ].…”

Section: C Elegans Models To Study the Function Of Appmentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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Section: C Elegans Models To Study the Function Of Appmentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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“…Although APP was originally identified in humans, it is actually a member of an evolutionarily ancient family of proteins that may serve similar roles in the developing nervous systems of many organisms ( Coulson et al, 2000 ; Ewald and Li, 2012 ; Lazarov and Demars, 2012 ; Shariati and De Strooper, 2013 ). Studies using a variety of insect models have shown that APPL shares both structural and functional conservation with human APP 695 , including homologous extracellular and intracellular motifs that regulate interactions with other proteins ( Cassar and Kretzschmar, 2016 ).…”

Section: App-gαo Signaling In the Control Of Neuronal Motility: Viewsmentioning

confidence: 99%

Role of APP Interactions with Heterotrimeric G Proteins: Physiological Functions and Pathological Consequences

Copenhaver

Kögel

2017

Front. Mol. Neurosci.

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Following the discovery that the amyloid precursor protein (APP) is the source of β-amyloid peptides (Aβ) that accumulate in Alzheimer's disease (AD), structural analyses suggested that the holoprotein resembles a transmembrane receptor. Initial studies using reconstituted membranes demonstrated that APP can directly interact with the heterotrimeric G protein Gαo (but not other G proteins) via an evolutionarily G protein-binding motif in its cytoplasmic domain. Subsequent investigations in cell culture showed that antibodies against the extracellular domain of APP could stimulate Gαo activity, presumably mimicking endogenous APP ligands. In addition, chronically activating wild type APP or overexpressing mutant APP isoforms linked with familial AD could provoke Go-dependent neurotoxic responses, while biochemical assays using human brain samples suggested that the endogenous APP-Go interactions are perturbed in AD patients. More recently, several G protein-dependent pathways have been implicated in the physiological roles of APP, coupled with evidence that APP interacts both physically and functionally with Gαo in a variety of contexts. Work in insect models has demonstrated that the APP ortholog APPL directly interacts with Gαo in motile neurons, whereby APPL-Gαo signaling regulates the response of migratory neurons to ligands encountered in the developing nervous system. Concurrent studies using cultured mammalian neurons and organotypic hippocampal slice preparations have shown that APP signaling transduces the neuroprotective effects of soluble sAPPα fragments via modulation of the PI3K/Akt pathway, providing a mechanism for integrating the stress and survival responses regulated by APP. Notably, this effect was also inhibited by pertussis toxin, indicating an essential role for Gαo/i proteins. Unexpectedly, C-terminal fragments (CTFs) derived from APP have also been found to interact with Gαs, whereby CTF-Gαs signaling can promote neurite outgrowth via adenylyl cyclase/PKA-dependent pathways. These reports offer the intriguing perspective that G protein switching might modulate APP-dependent responses in a context-dependent manner. In this review, we provide an up-to-date perspective on the model that APP plays a variety of roles as an atypical G protein-coupled receptor in both the developing and adult nervous system, and we discuss the hypothesis that disruption of these normal functions might contribute to the progressive neuropathologies that typify AD.

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The secreted Alzheimer-related amyloid precursor protein fragment has an essential role inC. elegans

Cited by 2 publications

References 25 publications

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Role of APP Interactions with Heterotrimeric G Proteins: Physiological Functions and Pathological Consequences

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