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Amyloid Precursor Protein
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Nigel M. Hooper – One of the best experts on this subject based on the ideXlab platform.
Soluble Amyloid Precursor Protein α: Friend or Foe?Advances in experimental medicine and biology, 2018Co-Authors: Nicola J. Corbett, Nigel M. HooperAbstract:
The “Amyloidogenic” proteolytic processing of the cell surface Amyloid Precursor Protein (APP) produces Amyloid-β, which causes a range of detrimental effects in the neuron, such as synaptic loss, and plays a key role in Alzheimer’s disease. In contrast, “non-Amyloidogenic” proteolytic processing, which involves the cleavage of APP by α-secretase, produces soluble Amyloid Precursor Protein α (sAPPα) and is the most predominant proteolytic processing of APP in the healthy brain. Current research suggests that sAPPα plays a role in synaptic growth and plasticity, but whether this role is protective or detrimental is age-dependent. This review looks at the effects of increasing sAPPα during three time-points in life (in development, young adult, ageing/neurodegeneration) when synaptic plasticity plays an important role.
The Amyloid Precursor Protein is not enriched in caveolae-like, detergent-insoluble membrane microdomains.Journal of neurochemistry, 2002Co-Authors: Edward T. Parkin, Ishrut Hussain, Anthony J. Turner, Nigel M. HooperAbstract:
The Amyloid Precursor Protein may be processed by several different pathways, one of which produces the Amyloid beta-peptpeptide betaA4 present in the Amyloid plaques characteristic of Alzheimer’s disease. A recent report suggested that axonal-Amyloid Precursor Protein is present in a membrane fraction “with caveolae-like properties.” In the present study we have isolated detergent-insoluble, caveolae-like membranes from both mouse cerebellum and the human neuroblastoma cell line SH-SY5Y. Detergent-insoluble membranes from mouse cerebellum retained nearly all of the glycosylphosphatidylinositol-anchored Proteins–alkaline phosphatase, 5′-nucleotidase, and the F3 Protein–while excluding the majority of the plasmalemmal marker Protein alkaline phosphodiesterase I. Although the inositol trisphosphate receptor was highly enriched in this detergent-insoluble fraction, neither Amyloid Precursor Protein nor clathrin immunoreactivity could be detected. Similar results were obtained with SH-SY5Y cells, where 5′-nucleotidase activity was enriched at least 30-fold in the detergent-insoluble membranes, but no Amyloid Precursor Protein or clathrin immunoreactivity could be detected. Caveolin could not be detected in microsomal membranes from either mouse cerebellum or SH-SY5Y cells. These observations suggest that Amyloid Precursor Protein is not normally present in detergent-insoluble, caveolae-like membrane microdomains.
Alzheimer’s Amyloid Precursor Protein alpha-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: similarities to the angiotensin converting enzyme secretase.Biochemistry, 1998Co-Authors: S. Parvathy, Ishrut Hussain, Eric Karran, A J Turner, Nigel M. HooperAbstract:
The 4 kDa beta-Amyloid peptide that forms the Amyloid fibrils in the brain parenchyma of Alzheimer’s disease patients is derived from the larger integral membrane Protein, the Amyloid Precursor Protein. In the nonAmyloidogenic pathway, alpha-secretase cleaves the Amyloid Precursor Protein within the beta-Amyloid domain, releasing an extracellular portion and thereby preventing deposition of the intact Amyloidogenic peptide. The release of the Amyloid Precursor Protein from both SH-SY5Y and IMR-32 neuronal cells by alpha-secretase was blocked by batimastat and other related synthetic hydroxamic acid-based zinc metalloprotease inhibitors, but not by the structurally unrelated zinc metalloprotease inhibitors enalaprilat and phosphoramidon. Batimastat inhibited the release of the Amyloid Precursor Protein from both cell lines with an I50 value of 3 microM. Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2′ substituent decreased the inhibitory potency of batimastat toward alpha-secretase. In the SH-SY5Y cells, both the basal and the carbachol-stimulated release of the Amyloid Precursor Protein were blocked by batimastat. In contrast, neither the level of full-length Amyloid Precursor Protein nor its cleavage by beta-secretase were inhibited by any of the zinc metalloprotease inhibitors examined. In transfected IMR-32 cells, the release of both the Amyloid Precursor Protein and angiotensin converting enzyme was inhibited by batimastat, marimastat, and BB2116 with I50 values in the low micromolar range, while batimastat and BB2116 inhibited the release of both Proteins from HUVECs. The profile of inhibition of alpha-secretase by batimastat and structurally related compounds is identical with that observed with the angiotensin converting enzyme secretase suggesting that the two are closely related zinc metalloproteases.
Masatoshi Takeda – One of the best experts on this subject based on the ideXlab platform.
Regional distribution of presenilin-1 messenger RNA in the embryonic rat brain: comparison with β-Amyloid Precursor Protein messenger RNA localizationNeuroscience, 1999Co-Authors: Hitoshi Tanimukai, Kohji Sato, Takashi Kudo, Yujiro Kashiwagi, Masaya Tohyama, Masatoshi TakedaAbstract:
The messenger RNA expression of presenilin-1, an important gene responsible for early-onset familial Alzheimer’s disease, was investigated in the embryonic rat brain with in situ hybridization histochemistry using an oligonucleotide probe specific to the messenger RNA. It was also compared with that of beta-Amyloid Precursor Protein messenger RNA. Presenilin-1 and beta-Amyloid Precursor Protein messenger RNA were abundantly expressed throughout the central nervous system in the embryonic day 13, 17 and 20 rat brain. Presenilin-1 messenger RNA was strongly expressed in both neuroepithelium and differentiating fields. In contrast, beta-Amyloid Precursor Protein messenger RNA was preferentially expressed in differentiating fields, while low expression of beta-Amyloid Precursor Protein messenger RNA was seen in neuroepithelium. Although the expression patterns of these two messenger RNAs were basically similar, there seemed to be a tendency that presenilin-1 messenger RNA was preferentially expressed in immature neurons, while beta-Amyloid Precursor Protein messenger RNA was preferentially expressed in mature neurons, suggesting that presenilin-1 is expressed earlier than beta-Amyloid Precursor Protein and that presenilin-1 is involved in beta-Amyloid Precursor Protein processing. These data raise the possibility that presenilin-1 and beta-Amyloid Precursor Protein co-operatively play pivotal roles in rat neurogenesis.
Ewa Hellström-lindahl – One of the best experts on this subject based on the ideXlab platform.
Modulation of β-Amyloid Precursor Protein processing and tau phosphorylation by acetylcholine receptorsEuropean Journal of Pharmacology, 2000Co-Authors: Ewa Hellström-lindahlAbstract:
Abstract Neurofibrillary lesions and senile plaques that are composed mainly of hyperphosphorylated tau Protein and the Amyloid-β peptide derived from the Amyloid Precursor Protein, respectively, are classical hallmarks of Alzheimer’s disease. A number of studies strongly suggests that Amyloid-β formation and Amyloid depositions are linked to the pathogenesis of Alzheimer’s disease. Recent findings suggest that very low concentrations of the Amyloid-β can inhibit various cholinergic neurotransmitter functions independently of apparent neurotoxicity. Many factors have been shown to influence the processing of Amyloid Precursor Protein, including activation of muscarinic and nicotinic receptors. This review focus on some recent studies concerning the regulation of Amyloid Precursor Protein processing and modulation of tau phosphorylation by acetylcholine receptor stimulation and how cholinergic deficits and Amyloid-β might be related to one another.
Modulation of beta-Amyloid Precursor Protein processing and tau phosphorylation by acetylcholine receptors.European journal of pharmacology, 2000Co-Authors: Ewa Hellström-lindahlAbstract:
Neurofibrillary lesions and senile plaques that are composed mainly of hyperphosphorylated tau Protein and the Amyloid-beta peptide derived from the Amyloid Precursor Protein, respectively, are classical hallmarks of Alzheimer’s disease. A number of studies strongly suggests that Amyloid-beta formation and Amyloid depositions are linked to the pathogenesis of Alzheimer’s disease. Recent findings suggest that very low concentrations of the Amyloid-beta can inhibit various cholinergic neurotransmitter functions independently of apparent neurotoxicity. Many factors have been shown to influence the processing of Amyloid Precursor Protein, including activation of muscarinic and nicotinic receptors. This review focus on some recent studies concerning the regulation of Amyloid Precursor Protein processing and modulation of tau phosphorylation by acetylcholine receptor stimulation and how cholinergic deficits and Amyloid-beta might be related to one another.
José M. Palacios – One of the best experts on this subject based on the ideXlab platform.
Differential regional and cellular distribution of β-Amyloid Precursor Protein messenger RNAs containing and lacking the kunitz protease inhibitor domain in the brain of human, rat and mouseNeuroscience, 1993Co-Authors: Carme Solà, Guadalupe Mengod, Alphonse Probst, José M. PalaciosAbstract:
Abstract The β-Amyloid Precursor Protein is the Precursor of the main component of senile plaques (the β-Amyloid peptide or β/A4) found in the brain of aged humans and, in higher amounts, in the brain of Alzheimer’s disease and Down’s syndrome subjects. Four different forms of β-Amyloid Precursor Protein messenger RNAs have been described in humans and rodents: β-Amyloid Precursor Protein 695, β-Amyloid Precursor Protein 714, β-Amyloid Precursor Protein 751 and β-Amyloid Precursor Protein 770 messenger RNAs (numbers corresponding to the number of encoded amino acids). The two latter forms are characterized by containing in their sequence a region with high homology to the Kunitz family of serine protease inhibitors. We have used oligonucleotide probes to study the distribution of the different messenger RNAs encoding each of the four β-Amyloid Precursor Proteins by in situ hybridization histochemistry in human, rat and mouse brain. We found that β-Amyloid Precursor Protein 695, β-Amyloid Precursor Protein 714 and β-Amyloid Precursor Protein 751 messenger RNAs were widely distributed in the human, rat and mouse brain and that their distribution was roughly similar in most brain areas in these three species. The distribution of β-Amyloid Precursor Protein 770 messenger RNA was not so wide and differed among the three species studied, β-Amyloid Precursor Protein 751 and 770 messenger RNAs were the only forms present at significant levels in rodent choroid plexus and meninges, while β-Amyloid Precursor Protein messenger RNA isoforms containing and lacking the Kunitz domain were detected in the human choroid plexus. We also observed that the relative levels of β-Amyloid Precursor Protein 751 and 770 messenger RNAs in the rat cerebral white matter as well as in the mouse and human striatum were higher than those of the β-Amyloid Precursor Protein messenger RNAs lacking the Kunitz domain. While the most abundant β-Amyloid Precursor Protein messenger RNAs in the brain of all three species under study were, in descending order, β-Amyloid Precursor Protein 695 and β-Amyloid Precursor Protein 751 messenger RNAs, the least abundant form was not the same for all species: in human it was β-Amyloid Precursor Protein 714 messenger RNA and in rat and mouse brain it was β-Amyloid Precursor Protein 770 messenger RNA. Our results show differences both inter- and intraspecies of the relative abundance and distribution of four β-Amyloid Precursor Protein messenger RNAs in rat, mouse and human brain. The non-coincidence of the distribution of β-Amyloid Precursor Protein messenger RNA isoforms suggests different physiological functions for the β-Amyloid Precursor Proteins. Interspecies differences should be considered when comparing results from animal and human studies.
Ulrike Müller – One of the best experts on this subject based on the ideXlab platform.
not just Amyloid physiological functions of the Amyloid Precursor Protein familyNature Reviews Neuroscience, 2017Co-Authors: Ulrike Müller, Thomas Deller, Martin KorteAbstract:
Amyloid Precursor Protein (APP) has been heavily implicated in Alzheimer disease, but the physiological roles of APP and the related APP-like Proteins (APLPs) remain less well understood. This Review examines the functions of the APP family and its fragments in CNS development, synaptic function, brain injury and ageing. Amyloid Precursor Protein (APP) gives rise to the Amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like Proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.
Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα.Frontiers in molecular neuroscience, 2017Co-Authors: Bruce G. Mockett, Max Richter, Wickliffe C. Abraham, Ulrike MüllerAbstract:
Cleavage of the Amyloid Precursor Protein by α-secretase generates an extracellularly released fragment termed secreted Amyloid Precursor Protein-alpha (APPsα). Not only is this process of interest due to the cleavage of APP within the Amyloid-beta sequence, but APPsα itself has many physiological properties that suggest its great potential as a therapeutic target. For example, APPsα is neurotrophic, neuroprotective, neurogenic, a stimulator of Protein synthesis and gene expression, and enhances long-term potentiation and memory. While most early studies have been conducted in vitro, effectiveness in animal models is now being confirmed. These studies have revealed that either upregulating α-secretase activity, acutely administering APPsα or chronic delivery of APPsα via a gene therapy approach can effectively treat mouse models of Alzheimer’s disease and other disorders such as traumatic head injury. Together these findings suggest the need for intensifying research efforts to harness the therapeutic potential of this multifunctional Protein.
The Functions of Mammalian Amyloid Precursor Protein and Related Amyloid Precursor-Like ProteinsNeuro-degenerative diseases, 2006Co-Authors: Brigitte Anliker, Ulrike MüllerAbstract: