p(HGNC:APP)
However, expression of either of the Asp 2 mutants does not produce the increase in the secretion of sAPPb (Fig. 2b) seen for wild-type Asp 2. In contrast to this clear effect on sAPPb, Asp 2 has no effect on the secretion of soluble APPa or on full-length APP in the cell (data not shown). PubMed:10656250
APP clearly localizes to the Golgi/endoplasmic reticulum region as revealed by distinctive juxtanuclear staining and a more generalized reticular staining throughout the cell (Figs. 6b and 6g). Asp 2 shows essentially the same subcellular distribution as revealed by simultaneous detection of myc-tagged Asp 2 and APP in COS-7 APP-751 cells (compare Figs. 6f and 6g), and merging of the confocal images for APP and Asp 2 indicates colocalization (Fig. 6h). PubMed:10656250
Activation of protein kinase C increases APPs α-secretion by mechanisms involving the formation and release of secretory vesicles from the TGN, thus enhancing APP (and possiblyα-secretase) trafficking to the cell surface. PubMed:18650430
In a similar fashion, released AICD has been shown to possess transactivation activity and can regulate transcription of multiple genes including APP, GSK- 3b, KAI1, neprilysin, BACE1, p53, EGFR, and LRP1 [127-132] PubMed:21214928
APP undergoes rapid anterograde transport in neurons PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
Moreover, internalization of APP from the cell surface for endosomal/lysosomal degradation can be mediated by clathrin PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
Antagonizing the extracellular interaction between cell-surface APP and LRP increased the level of cell surface APP while decreasing Abeta generation [187] PubMed:21214928
This PS1-PLD1 interaction recruits PLD1 to the Golgi/TGN and thus potentially alters APP trafficking as PLD1 overexpression promotes budding of vesicles from the TGN containing APP and increases cell surface levels of APP [176,177] PubMed:21214928
We and others have shown that PS1 can also regulate the intracellular trafficking of APP PubMed:21214928
APP was found to colocalize with beta1 intergrins in neural cells [23] PubMed:21214928
The extracellular portion of APP contains E1 and E2 domains and a Kunitz protease inhibitor (KPI) domain that is missing in APP695 (Kang and Muller-Hill 1990; Rohan de Silva et al. 1997) PubMed:22122372
The extracellular portion of APP contains E1 and E2 domains and a Kunitz protease inhibitor (KPI) domain that is missing in APP695 (Kang and Muller-Hill 1990; Rohan de Silva et al. 1997) PubMed:22122372
Because of its highly similar structure to Notch, APP has been proposed to function as a cell surface receptor (reviewed in Zheng and Koo 2011) PubMed:22122372
APP can also be cleaved by alpha-secretase to form a soluble or secreted APP ectodomain (sAPP-alpha) that has been shown to be mostly neuro-protective PubMed:22122372
In fact, it has been shown that APP interacts with CHT1 proteins increasing their endocytosis from the cell surface [258] and that mice that display disruption of CHT1 gene expression exhibit symptoms related to ACh deficit PubMed:26813123
Abeta, an important player in AD, is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases: APP is cleaved by beta-secretase (BACE1) to generate the large secreted derivative sAPPbeta and the membrane-bound APP C-terminal fragment-beta; the latter can be further cleaved by gamma-secretase to generate Abeta and APP intracellular domain. Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain, which precludes Abeta production and instead generates secreted sAPPalpha that has been shown to be neuroprotective PubMed:24590577
Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface PubMed:24590577
Abeta, an important player in AD, is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases: APP is cleaved by beta-secretase (BACE1) to generate the large secreted derivative sAPPbeta and the membrane-bound APP C-terminal fragment-beta; the latter can be further cleaved by gamma-secretase to generate Abeta and APP intracellular domain. Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain, which precludes Abeta production and instead generates secreted sAPPalpha that has been shown to be neuroprotective PubMed:24590577
The Ab peptide is generated by the sequential cleavage of the amyloid precursor protein (APP) by the b and g secretases, resulting in the generation of peptides 40 or 42 amino acids in length [2]. PubMed:21718217
The Ab peptide is generated by the sequential cleavage of the amyloid precursor protein (APP) by the b and g secretases, resulting in the generation of peptides 40 or 42 amino acids in length [2]. PubMed:21718217
This mutation at codon 670/671 on the APP gene on chromosome 21 was discovered in a Swedish family, and the mutation is unique in the sense that it is the only AD mutation that has been shown to alter the APP metabolism, resulting in an overexpression of the amyloid leading to plaque formation (Mullan et al 1992) PubMed:11230871
Tau, α-synuclein and TDP43 are substrates for CMA degradation, as are amyloid precursor protein (APP) but not amyloid-β fragment 42 (Aβ42) itself 3,45–47,48 . PubMed:30116051
AK1 also increased in the hippocampus of APP-J20, an AD model mouse expressing familial AD-mutant APP (Supple- mentary Material, Fig. S1A and B). PubMed:22419736
Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56 PubMed:26195256
Extracellular degradation of ISF proteins mainly consists of degradation by proteases expressed and secreted by cells such as astrocytes PubMed:26195256
Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56 PubMed:26195256
ecifically, Aβ accumulation into extracellular plaques is marked by decreased CSF levels of Aβ1–42, and tau accumulation into NFTs is marked by increased CSF levels of total tau and hyperphosphory- lated tau. PubMed:26195256
Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56 PubMed:26195256
Emerging evidence suggests that Aβ clearance is impaired in both early-onset and late-onset forms of AD. PubMed:26195256
In contrast, the DAPK1 fragments from 1 to 1423, from 637 to 1423 and from 848 to 1423 efficiently bound to APP, suggesting that the death domain (1271–1423, DD) is likely bound to APP (Fig. 4F). PubMed:27094130
In contrast, the DAPK1 fragments from 1 to 1423, from 637 to 1423 and from 848 to 1423 efficiently bound to APP, suggesting that the death domain (1271–1423, DD) is likely bound to APP (Fig. 4F). PubMed:27094130
In contrast, the DAPK1 fragments from 1 to 1423, from 637 to 1423 and from 848 to 1423 efficiently bound to APP, suggesting that the death domain (1271–1423, DD) is likely bound to APP (Fig. 4F). PubMed:27094130
NO can also bring about apoptosis of hippocampal neurons via caspase- 3 activity [50] whereas astrocyte-secreted IL-1 beta can increase the production of APP and A beta from neu- rons [51–53] (Fig. 1). PubMed:27314526
Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36 Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD. PubMed:30444369
Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809
However, it is believed that the secreted form of APP plays important roles in neuronal plasticity and survival (Mattson, 1997). PubMed:12428809
However, it is believed that the secreted form of APP plays important roles in neuronal plasticity and survival (Mattson, 1997). PubMed:12428809
AVs are also enriched in APP substrates and secretases and, during autophagy, Ab peptide is generated from APP (Yu et al. 2005), although it is subsequently degraded in lysosomes under normal circumstances (Heinrich et al. 1999; Bahr et al. 2002; Florez-McClure et al. 2007). PubMed:22908190
In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.). PubMed:22908190
In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.). PubMed:22908190
Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136
Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136
We have previously shown that racemic nilvadipine affects the β-cleavage of APP and reduces sAPPβ secretion PubMed:25331948
This study revealed that tau deficiency can cause iron accumulation inside neurons by preventing the trafficking of APP to the cell surface, where APP usually interacts with ferroportin (FPN) to facilitate the export of iron PubMed:26631930
By attaching to the 3′‐UTR sequence, the miR‐153 reduces the expression of the APP PubMed:30663117
Downregulation of miR‐153 increases the expression of APP and eventually, the production of β‐ameloid is promoted, increasing the risk of AD PubMed:30663117
It was found that miR‐384, by binding to the 3′‐UTR sequence on BACE1 mRNA, could not only reduce expression in SH‐SY5Y cells but also attach to the 3′‐UTR sequence of the mRNA APP and reduce its expression, and this highlights the importance of miR‐384 in AD PubMed:30663117
On the other hand, miR‐101, by downregulating RanBP9, can indirectly reduce the production of APP PubMed:30663117
Besides, by directly affecting APP, miR‐101 can cause its downregulation, which ultimately provides the basis for AD PubMed:30663117
One of these factors is Ran‐binding protein 9 (RanBP9) that can increase the amount of APP in the cell by its effects PubMed:30663117
There was no significant difference in APP level between p65 transfected cells and controls (p>0.05). PubMed:21329555
Indeed, Checler and colleagues have shown in a recent study that, NF-κB mediates the Amyloid-β – induced increase in expression of AβPP in HEK293 cells PubMed:28745240
Furthermore, two κB-binding sites have been identified in the proximal promoter region of AβPP, suggesting the potential regulation of AβPP expression by NF-κB PubMed:28745240
Indeed, Checler and colleagues have shown in a recent study that, NF-κB mediates the Amyloid-β – induced increase in expression of AβPP in HEK293 cells PubMed:28745240
What's more, DLPC complete- ly abolishes TNF-α and H 2 O 2 induced neuronal tau phosphorylation, re- duces cellular APP levels and Aβ expression and secretion in SH-SY5Y cells [91,92] (Table 1). PubMed:27288790
In neuronal cells Aβ1-42 peptide has been shown to regulate APP and BACE1 proteins in NF-κB dependent manner PubMed:25652642
In neuronal cells Aβ1-42 peptide has been shown to regulate APP and BACE1 proteins in NF-κB dependent manner PubMed:25652642
Furthermore, APP also regulates the presynaptic expression and activity of the high affinity choline transporter. PubMed:18650430
APP did though potentiate both Wnt3a-driven Wnt-β-catenin signalling and Wnt5a-driven Wnt-PCP signalling. PubMed:30232325
APP did though potentiate both Wnt3a-driven Wnt-β-catenin signalling and Wnt5a-driven Wnt-PCP signalling. PubMed:30232325
In contrast with wild-type APP which, as before, potentiated both canonical and non-canonical Wnt signalling, the Swedish mutant form of APP antagonised canonical Wnt signalling (Fig. 2a), and potentiated non-canonical Wnt signalling to a greater degree than wild-type APP (APPWT) (Fig. 2b). PubMed:30232325
In contrast with wild-type APP which, as before, potentiated both canonical and non-canonical Wnt signalling, the Swedish mutant form of APP antagonised canonical Wnt signalling (Fig. 2a), and potentiated non-canonical Wnt signalling to a greater degree than wild-type APP (APPWT) (Fig. 2b). PubMed:30232325
Overexpression of APP enhanced the inhibitory effects of Dkk1 on Wnt3a induced Wnt-β-catenin signalling, counteracting the enhanced activity resulting from APP overexpression and reducing the IC50 of Dkk1 to 122ng/mL from 173ng/mL in the absence of APP (Fig. 2f) . PubMed:30232325
In contrast, the stimulatory effects of Dkk1 on WntPCP signalling induced by Wnt5a were enhanced by APP overexpression, decreasing the EC50 of Dkk1 to 599ng/ mL from 1405ng/mL (Fig. 2g). PubMed:30232325
Aβ synaptoxicity is Dkk1-dependent12,24 and also appears to be APP-dependent25. PubMed:30232325
APP clearly localizes to the Golgi/endoplasmic reticulum region as revealed by distinctive juxtanuclear staining and a more generalized reticular staining throughout the cell (Figs. 6b and 6g). Asp 2 shows essentially the same subcellular distribution as revealed by simultaneous detection of myc-tagged Asp 2 and APP in COS-7 APP-751 cells (compare Figs. 6f and 6g), and merging of the confocal images for APP and Asp 2 indicates colocalization (Fig. 6h). PubMed:10656250
Because, as mentioned above, APPs is constitutively released from cells following α-secretase cleavage, these find- ings indicated that APP has autocrine and paracrine functions in growth regulation. PubMed:18650430
The N-terminal heparin-binding domain of APP (res- idues 28–123) upstream from the RERMS sequence also stim- ulates neurite outgrowth and promotes synaptogenesis. PubMed:18650430
The N-terminal heparin-binding domain of APP (res- idues 28–123) upstream from the RERMS sequence also stim- ulates neurite outgrowth and promotes synaptogenesis. PubMed:18650430
An RHDS motif near the extralumenal por- tion of APP or at the C terminus of APPs lying within the Aβ region appears to promote cell adhesion. PubMed:18650430
Abeta is generated from b-amyloid precursor protein (APP) through sequential cleavages first by beta-secretase and then by gamma-secretase complex PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19]) PubMed:21214928
Overall, most studies suggest that APP plays some role in regulating protein trafficking PubMed:21214928
APP was found to colocalize with beta1 intergrins in neural cells [23] PubMed:21214928
APP undergoes rapid anterograde transport in neurons PubMed:21214928
APP undergoes post-translational proteolysis/processing to generate the hydrophobic beta-amyloid (Abeta) peptides PubMed:22122372
Cloning of the complementary DNA (cDNA) of Abeta revealed that Abeta is derived from a larger precursor protein (Tanzi et al. 1987) PubMed:22122372
The extracellular portion of APP contains E1 and E2 domains and a Kunitz protease inhibitor (KPI) domain that is missing in APP695 (Kang and Muller-Hill 1990; Rohan de Silva et al. 1997) PubMed:22122372
The extracellular portion of APP contains E1 and E2 domains and a Kunitz protease inhibitor (KPI) domain that is missing in APP695 (Kang and Muller-Hill 1990; Rohan de Silva et al. 1997) PubMed:22122372
Because of its highly similar structure to Notch, APP has been proposed to function as a cell surface receptor (reviewed in Zheng and Koo 2011) PubMed:22122372
Nevertheless, APP is more widely accepted as a protein contributing to cell adhesion via its extracellular domain PubMed:22122372
This mutation at codon 670/671 on the APP gene on chromosome 21 was discovered in a Swedish family, and the mutation is unique in the sense that it is the only AD mutation that has been shown to alter the APP metabolism, resulting in an overexpression of the amyloid leading to plaque formation (Mullan et al 1992) PubMed:11230871
The plaques in AD are rich in amyloid beta peptides (Abeta) that are produced by proteolytic cleavage of the amyloid precursor peptide (APP), a glycolipid located in the outer cell membrane PubMed:14556719
AK1 also increased in the hippocampus of APP-J20, an AD model mouse expressing familial AD-mutant APP (Supple- mentary Material, Fig. S1A and B). PubMed:22419736
ecifically, Aβ accumulation into extracellular plaques is marked by decreased CSF levels of Aβ1–42, and tau accumulation into NFTs is marked by increased CSF levels of total tau and hyperphosphory- lated tau. PubMed:26195256
In contrast, the DAPK1 fragments from 1 to 1423, from 637 to 1423 and from 848 to 1423 efficiently bound to APP, suggesting that the death domain (1271–1423, DD) is likely bound to APP (Fig. 4F). PubMed:27094130
In contrast, the DAPK1 fragments from 1 to 1423, from 637 to 1423 and from 848 to 1423 efficiently bound to APP, suggesting that the death domain (1271–1423, DD) is likely bound to APP (Fig. 4F). PubMed:27094130
In contrast, the DAPK1 fragments from 1 to 1423, from 637 to 1423 and from 848 to 1423 efficiently bound to APP, suggesting that the death domain (1271–1423, DD) is likely bound to APP (Fig. 4F). PubMed:27094130
Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809
However, it is believed that the secreted form of APP plays important roles in neuronal plasticity and survival (Mattson, 1997). PubMed:12428809
However, it is believed that the secreted form of APP plays important roles in neuronal plasticity and survival (Mattson, 1997). PubMed:12428809
Aβ peptides originate from the transmembrane protein amyloid precursor protein (APP) which undergoes sequential cleavage via two distinct pathways by the enzyme complexes β- and γ-secretase [31] PubMed:29758300
In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.). PubMed:22908190
In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.). PubMed:22908190
In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.). PubMed:22908190
AVs are also enriched in APP substrates and secretases and, during autophagy, Ab peptide is generated from APP (Yu et al. 2005), although it is subsequently degraded in lysosomes under normal circumstances (Heinrich et al. 1999; Bahr et al. 2002; Florez-McClure et al. 2007). PubMed:22908190
Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136
This study revealed that tau deficiency can cause iron accumulation inside neurons by preventing the trafficking of APP to the cell surface, where APP usually interacts with ferroportin (FPN) to facilitate the export of iron PubMed:26631930
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