The physiological functions of the β-amyloid precursor protein APP

Müller, Ulrike; Pietrzik, Claus U.; Deller, Thomas

doi:10.1007/s00221-012-3039-2

Cited by 14 publications

(11 citation statements)

References 17 publications

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“…This molecule is sequentially cleaved by β-site APP-cleaving enzyme (BACE)-1 and γ-secretase to generate Aβ peptides that accumulate in the brains of AD patients. 1 Presently, 33 APP mutations are known to result in amyloid accumulation ( http://www.molgen.vib-ua.be/AD Mutations). APP is ubiquitously expressed in cells throughout the body and its proteolytic products are thought to be involved in many functions such as the modulation of neuroprotection, neurogenesis, neuronal differentiation and migration, cell adhesion, synapse formation, neurite outgrowth, regulation of transcription, axonal transport, 2 and regulation of the coagulation cascade.…”

Section: Introductionmentioning

confidence: 99%

Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis

et al. 2013

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Transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been extensively used to study the pathophysiology of this dementia and to test the efficacy of drugs to treat AD. The 5XFAD Tg mouse, which contains two presenilin-1 and three amyloid precursor protein (APP) mutations, was designed to rapidly recapitulate a portion of the pathologic alterations present in human AD. APP and its proteolytic peptides, as well as apolipoprotein E and endogenous mouse tau, were investigated in the 5XFAD mice at 3 months, 6 months, and 9 months. AD and nondemented subjects were used as a frame of reference. APP, amyloid-beta (Aβ) peptides, APP C-terminal fragments (CT99, CT83, AICD), β-site APP-cleaving enzyme, and APLP1 substantially increased with age in the brains of 5XFAD mice. Endogenous mouse tau did not show age-related differences. The rapid synthesis of Aβ and its impact on neuronal loss and neuroinflammation make the 5XFAD mice a desirable paradigm to model AD.

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Section: Introductionmentioning

confidence: 99%

Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis

et al. 2013

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“… 4 , 5 APP is a multifunctional protein implicated in several physiologic processes, including neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis and cell survival. 1 , 6 Therefore, loss of these physiologic APP functions might be implicated in reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging, which ultimately may lead to neurodegeneration. In line with this notion, decreased levels of soluble APPs were detected in the cerebrospinal fluid of patients with Alzheimer's disease (AD).…”

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confidence: 99%

Holo-APP and G-protein-mediated signaling are required for sAPPα-induced activation of the Akt survival pathway

et al. 2014

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Accumulating evidence indicates that loss of physiologic amyloid precursor protein (APP) function leads to reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. Here we investigated the neuroprotective function of the soluble APP ectodomain sAPPα (soluble APPα), which is generated by cleavage of APP by α-secretase along the non-amyloidogenic pathway. Recombinant sAPPα protected primary hippocampal neurons and SH-SY5Y neuroblastoma cells from cell death induced by trophic factor deprivation. We show that this protective effect is abrogated in neurons from APP-knockout animals and APP-depleted SH-SY5Y cells, but not in APP-like protein 1- and 2- (APLP1 and APLP2) depleted cells, indicating that expression of membrane-bound holo-APP is required for sAPPα-dependent neuroprotection. Trophic factor deprivation diminished the activity of the Akt survival pathway. Strikingly, both recombinant sAPPα and the APP-E1 domain were able to stimulate Akt activity in wild-type (wt) fibroblasts, SH-SY5Y cells and neurons, but failed to rescue in APP-deficient neurons or fibroblasts. The ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) inhibitor GI254023X exacerbated neuron death in organotypic (hippocampal) slice cultures of wt mice subjected to trophic factor and glucose deprivation. This cell death-enhancing effect of GI254023X could be completely rescued by applying exogenous sAPPα. Interestingly, sAPPα-dependent Akt induction was unaffected in neurons of APP-ΔCT15 mice that lack the C-terminal YENPTY motif of the APP intracellular region. In contrast, sAPPα-dependent rescue of Akt activation was completely abolished in APP mutant cells lacking the G-protein interaction motif located in the APP C-terminus and by blocking G-protein-dependent signaling with pertussis toxin. Collectively, our data provide new mechanistic insights into the physiologic role of APP in antagonizing neurotoxic stress: they suggest that cell surface APP mediates sAPPα-induced neuroprotection via G-protein-coupled activation of the Akt pathway.

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“…cell-matrix interactions permits osteoblast differentiation 4 ). The Amyloid beta precursor protein, a transmembrane protein that can be cleaved by a secretase and released in the ECM 51 , has the highest value of betweenness centrality (Figure 4d). This protein regulates osteoclast function (affecting bone remodeling) and is present in both bone and brain and can link osteoporosis and neurodegenerative diseases 52,53 .…”

Section: Protein Interaction Network Of Bone Ecm Proteins In Humanmentioning

confidence: 99%

Phylobone: A comprehensive database of bone extracellular matrix proteins in human and model organisms

Fontcuberta-Rigo

Nakamura

Puigbò

2023

Preprint

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The bone extracellular matrix (ECM) contains minerals deposited on highly crosslinked collagen fibrils and hundreds of non-collagenous proteins. Some of these proteins are key to the regulation of bone formation and regeneration via signaling pathways, and play important regulatory and structural roles. However, the complete list of bone extracellular matrix proteins, their roles, and the extent of individual and cross-species variations have not been fully captured in both humans and model organisms. Here, we introduce the most comprehensive resource of bone extracellular matrix (ECM) proteins that can be used in research fields such as bone regeneration, osteoporosis, and mechanobiology. The Phylobone database (available at https://phylobone.com) includes 255 proteins potentially expressed in the bone extracellular matrix (ECM) of humans and 30 species of vertebrates. A bioinformatics pipeline was used to identify the evolutionary relationships of bone ECM proteins. The analysis facilitated the identification of potential model organisms to study the molecular mechanisms of bone regeneration. A network analysis showed high connectivity of bone ECM proteins. A total of 214 functional protein domains were identified, including collagen and the domains involved in bone formation and resorption. Information from public drug repositories was used to identify potential repurposing of existing drugs. The Phylobone database provides a platform to study bone regeneration and osteoporosis in light of (biological) evolution, and will substantially contribute to the identification of molecular mechanisms and drug targets.

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The physiological functions of the β-amyloid precursor protein APP

Cited by 14 publications

References 17 publications

Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis

Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis

Holo-APP and G-protein-mediated signaling are required for sAPPα-induced activation of the Akt survival pathway

Phylobone: A comprehensive database of bone extracellular matrix proteins in human and model organisms

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