Genomes and Genes
amyloid beta protein precursor
Summary: A single-pass type I membrane protein. It is cleaved by AMYLOID PRECURSOR PROTEIN SECRETASES to produce peptides of varying amino acid lengths. A 39-42 amino acid peptide, AMYLOID BETA-PEPTIDES is a principal component of the extracellular amyloid in SENILE PLAQUES.
- Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima Kawashima M, Funamoto S, et al. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009;29:13042-52 pubmed publisher..According to numerical simulation based on the successive reaction kinetics, the induction period exists. These results strongly suggest that Abeta is generated through the stepwise processing of betaCTF by gamma-secretase. ..
- Goodger Z, Rajendran L, Trutzel A, Kohli B, Nitsch R, Konietzko U. Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci. 2009;122:3703-14 pubmed publisher..This suggests that amyloidogenic cleavage, despite representing the minor cleavage pathway of APP, is predominantly responsible for AICD-mediated nuclear signaling. ..
- Braithwaite S, Schmid R, He D, Sung M, Cho S, Resnick L, et al. Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease. Neurobiol Dis. 2010;39:311-7 pubmed publisher..Our findings demonstrate that Abeta can induce neurodegeneration, at least in part, through the JNK pathway and suggest that inhibition of JNK may be of therapeutic utility in the treatment of AD. ..
- Hou Y, Yu Y, Liu G, Luo Y. A natural squamosamide derivative FLZ reduces amyloid-beta production by increasing non-amyloidogenic AbetaPP processing. J Alzheimers Dis. 2009;18:153-65 pubmed publisher..These findings suggest that FLZ reduces Abeta production by promoting AbetaPP non-amyloidogenic alpha-secretase processing. As such, FLZ may have therapeutic potential for the treatment of AD...
- Duce J, Tsatsanis A, Cater M, James S, Robb E, Wikhe K, et al. Iron-export ferroxidase activity of ?-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010;142:857-67 pubmed publisher..Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD. ..
- Munter L, Botev A, Richter L, Hildebrand P, Althoff V, Weise C, et al. Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif. J Biol Chem. 2010;285:21636-43 pubmed publisher..Our results contribute to a general understanding of the mechanism how APP is processed by the gamma-secretase module and strongly emphasize the potential of the GxxxG motif in the prevention of sporadic AD as well as FAD. ..
- Kiyota T, Okuyama S, Swan R, Jacobsen M, Gendelman H, Ikezu T. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J. 2010;24:3093-102 pubmed publisher..Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Abeta-mediated treatment of AD. ..
- Walton J, Wang M. APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer's disease. J Inorg Biochem. 2009;103:1548-54 pubmed publisher..Aluminum may thus launch the cascade that results in the formation of amyloid plaques in human brain. ..
- Chen B, Bromley Brits K, He G, Cai F, Zhang X, Song W. Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer's disease mouse model. Curr Alzheimer Res. 2010;7:255-61 pubmed..Our study showed that synthetic cannabinoid HU210 had no beneficial effects on AD neuropathology and behavioral deficits of AD model mice, which advises caution of such drug's application in AD therapies. ..
- Tong M, Neusner A, Longato L, Lawton M, Wands J, de la Monte S. Nitrosamine exposure causes insulin resistance diseases: relevance to type 2 diabetes mellitus, non-alcoholic steatohepatitis, and Alzheimer's disease. J Alzheimers Dis. 2009;17:827-44 pubmed..Improved detection and prevention of human exposures to nitrosamines will lead to earlier treatments and eventual quelling of these costly and devastating epidemics. ..
- Gimbel D, Nygaard H, Coffey E, Gunther E, Lauren J, Gimbel Z, et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci. 2010;30:6367-74 pubmed publisher..Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C). ..
- Duce J, Bush A. Biological metals and Alzheimer's disease: implications for therapeutics and diagnostics. Prog Neurobiol. 2010;92:1-18 pubmed publisher..Accordingly, assisting the balance of metal ions back to homeostatic levels has been proposed as a disease-modifying therapeutic strategy for Alzheimer's disease as well as other neurodegenerative diseases. ..
- Austin S, Sens M, Combs C. Amyloid precursor protein mediates a tyrosine kinase-dependent activation response in endothelial cells. J Neurosci. 2009;29:14451-62 pubmed publisher..These APP-mediated events may serve as therapeutic targets for intervention in progressive vascular changes common to cerebrovascular disease and AD. ..
- Joshi P, Liang J, DiMonte K, Sullivan J, Pimplikar S. Amyloid precursor protein is required for convergent-extension movements during Zebrafish development. Dev Biol. 2009;335:1-11 pubmed publisher..Collectively, this work demonstrates that the zebrafish model is a powerful system to define the role of APP during embryonic development and to evaluate the functional activity of fAD mutant APP. ..
- Fonseca A, Resende R, Oliveira C, Pereira C. Cholesterol and statins in Alzheimer's disease: current controversies. Exp Neurol. 2010;223:282-93 pubmed publisher..Because of the high number of pleiotropic effects of statins, novel molecular mechanisms that account for the beneficial effect of these drugs on AD might be discovered in a near future. ..
- Pérez Revuelta B, Fukumori A, Lammich S, Yamasaki A, Haass C, Steiner H. Requirement for small side chain residues within the GxGD-motif of presenilin for gamma-secretase substrate cleavage. J Neurochem. 2010;112:940-50 pubmed publisher..These findings broaden our understanding of gamma-secretase substrate recognition and cleavage, which may prove crucial for therapeutic targeting of the enzyme. ..
- Mancuso M, Orsucci D, Logerfo A, Calsolaro V, Siciliano G. Clinical features and pathogenesis of Alzheimer's disease: involvement of mitochondria and mitochondrial DNA. Adv Exp Med Biol. 2010;685:34-44 pubmed
- Harris J, Devidze N, Halabisky B, Lo I, Thwin M, Yu G, et al. Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci. 2010;30:372-81 pubmed publisher..Thus, caspase cleavage of APP at position D664 and generation of C31 do not play a critical role in the development of these abnormalities. ..
- Mitchell J, Perkinton M, Yates D, Lau K, Rogelj B, Miller C, et al. Expression of the neuronal adaptor protein X11alpha protects against memory dysfunction in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2010;20:31-6 pubmed publisher..However, X11alpha reduced brain Abeta levels and corrected spatial reference memory defects in aged X11alpha/AbetaPP double transgenics. Thus, X11alpha may be a therapeutic target for Alzheimer's disease. ..
- Grösgen S, Grimm M, Friess P, Hartmann T. Role of amyloid beta in lipid homeostasis. Biochim Biophys Acta. 2010;1801:966-74 pubmed publisher..Additionally, mutual influence of lipids and APP processing raises the question if altered lipid homeostasis is the cause or consequence of AD. ..
- Concepcion G, Padlan E. Does the electrical activity of neurons contribute to the pathogenesis of Alzheimer's Disease?. Med Hypotheses. 2010;74:27-8 pubmed publisher..We propose that the electrical activity of neurons causes a structural destabilization of the fragments, which could lead to fibril formation, and thereby contributes to the pathogenesis of Alzheimer's Disease. ..
- Rustay N, Cronin E, Curzon P, Markosyan S, Bitner R, Ellis T, et al. Mice expressing the Swedish APP mutation on a 129 genetic background demonstrate consistent behavioral deficits and pathological markers of Alzheimer's disease. Brain Res. 2010;1311:136-47 pubmed publisher..These results indicate that mice on the 129 genetic background may generate more consistent and robust behavioral differences, providing a useful model for testing therapeutic agents for Alzheimer's disease. ..
- Wang Y, Valadares D, Sun Y, Wang X, Zhong J, Liu X, et al. Effects of proNGF on neuronal viability, neurite growth and amyloid-beta metabolism. Neurotox Res. 2010;17:257-67 pubmed publisher..proNGF is localized to the Abeta plaques in AD mice brain, however, it had no significant effect on Abeta production in vitro and in vivo. Our findings suggest that proNGF is an important factor involving AD pathogenesis. ..
- Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, et al. Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci. 2009;29:10788-801 pubmed publisher..We postulate that transsynaptic APP interaction modulates its synaptic function and that perturbed APP synaptic adhesion activity may contribute to synaptic dysfunction and AD pathogenesis. ..
- Spuch C, Antequera D, Isabel Fernandez Bachiller M, Isabel Rodríguez Franco M, Carro E. A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer's disease. Neurotox Res. 2010;17:421-31 pubmed publisher..Since this tacrine-melatonin hybrid apparently reduces brain Abeta and behavioral deficits, we believe this drug has remarkable and significant neuroprotective effects and might be considered a potential therapeutic strategy in AD. ..
- Placanica L, Chien J, Li Y. Characterization of an atypical gamma-secretase complex from hematopoietic origin. Biochemistry. 2010;49:2796-804 pubmed publisher..These data underscore the need for studying endogenous gamma-secretase to fully understand of the biology of gamma-secretase and its complexity as a molecular target for the development of disease therapeutics. ..
- Zheng W, Wang T, Yu D, Feng W, Nie Y, Stoltenberg M, et al. Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AbetaPP/PS1 transgenic mouse. J Alzheimers Dis. 2010;20:323-31 pubmed publisher..Collectively, our results suggest that ZnT3 protein is involved in the Abeta aggregation in the cerebellum of the AbetaPP/PS1 mouse. ..
- Irobi J, Almeida Souza L, Asselbergh B, de Winter V, Goethals S, Dierick I, et al. Mutant HSPB8 causes motor neuron-specific neurite degeneration. Hum Mol Genet. 2010;19:3254-65 pubmed publisher..These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L. ..
- Butterfield D, Galvan V, Lange M, Tang H, Sowell R, Spilman P, et al. In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid beta-peptide of APP. Free Radic Biol Med. 2010;48:136-44 pubmed publisher..However, in this specific transgenic mouse model of AD, oxidative stress is neither required nor sufficient for memory abnormalities. ..
- Buoso E, Lanni C, Schettini G, Govoni S, Racchi M. beta-Amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain. Pharmacol Res. 2010;62:308-17 pubmed publisher..Our work is aimed to analyse the functional role of AICD, integrating also the AICD degradation processes, to better define a potential role of AICD in signal transduction. ..
- Lee E, Kim H, Kuwano Y, Abdelmohsen K, Srikantan S, Subaran S, et al. hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol. 2010;17:732-9 pubmed publisher..Our findings indicate that FMRP represses translation by recruiting APP mRNA to processing bodies, whereas hnRNP C promotes APP translation by displacing FMRP, thereby relieving the translational block. ..
- Li H, Wang B, Wang Z, Guo Q, Tabuchi K, Hammer R, et al. Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc Natl Acad Sci U S A. 2010;107:17362-7 pubmed publisher..This unexpected APP-mediated signaling pathway may play an important role in maintaining TTR and Klotho levels and their respective functions in A? sequestration and aging. ..
- Westmark C, Westmark P, Malter J. Alzheimer's disease and Down syndrome rodent models exhibit audiogenic seizures. J Alzheimers Dis. 2010;20:1009-13 pubmed publisher..Our data strongly implicates AbetaPP or a catabolite in seizure susceptibility and suggests that mGluR5 mediates this response. ..
- Endres K, Fahrenholz F. Upregulation of the alpha-secretase ADAM10--risk or reason for hope?. FEBS J. 2010;277:1585-96 pubmed publisher..The present review summarizes our knowledge about the structure and function of ADAM10 and highlights the opportunities for enhancing the expression and/or activity of the alpha-secretase as a therapeutic target. ..
- Wei W, Nguyen L, Kessels H, Hagiwara H, Sisodia S, Malinow R. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci. 2010;13:190-6 pubmed publisher..Notably, only 30-60 min blockade of Abeta overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Abeta at dendrites or axons acts locally to reduce the number and plasticity of synapses. ..
- Alley G, Bailey J, Chen D, Ray B, Puli L, Tanila H, et al. Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP/PS1 transgenic mice. J Neurosci Res. 2010;88:143-54 pubmed publisher..Memantine's ability to preserve neuronal cells against neurodegeneration, to increase metabolic activity, and to lower Abeta level has therapeutic implications for neurodegenerative disorders. ..
- Lenzken S, Stanga S, Lanni C, De Leonardis F, Govoni S, Racchi M. Recruitment of casein kinase 2 is involved in AbetaPP processing following cholinergic stimulation. J Alzheimers Dis. 2010;20:1133-41 pubmed publisher..On the basis of our results, we add another player to the complex cellular mechanisms regulating non-amyloidogenic processing of AbetaPP. ..
- Vilardo E, Barbato C, Ciotti M, Cogoni C, Ruberti F. MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem. 2010;285:18344-51 pubmed publisher..Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of Abeta, suggesting a possible role for miR-101 in neuropathological conditions. ..
- Zhang C, Browne A, Kim D, Tanzi R. Familial Alzheimer's disease mutations in presenilin 1 do not alter levels of the secreted amyloid-beta protein precursor generated by beta-secretase cleavage. Curr Alzheimer Res. 2010;7:21-6 pubmed..All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPPbeta levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPPbeta. ..
- Lin J, Li X, Yuan F, Lin L, Cook C, Rao C, et al. Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2010;69:253-61 pubmed publisher..The APPsw(+)/Lhr(-/-) mouse may be a useful tool for advancing understanding of the role of LH-mediated events in Alzheimer disease and a model in which to test therapeutic interventions. ..
- Garcia P, Youssef I, Utvik J, Florent Béchard S, Barthélémy V, Malaplate Armand C, et al. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease. J Neurosci. 2010;30:7516-27 pubmed publisher..Our data also encourage additional exploration of ex vivo gene transfer for the prevention and/or treatment of AD. ..
- Peng Y, Sun J, Hon S, Nylander A, Xia W, Feng Y, et al. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer's disease. J Neurosci. 2010;30:8180-9 pubmed publisher..L-NBP shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer's disease. ..
- Lu J, Joseph J, Nash R, Storek J, Stevens A, Metz L, et al. Neuroinflammation and demyelination in multiple sclerosis after allogeneic hematopoietic stem cell transplantation. Arch Neurol. 2010;67:716-22 pubmed publisher..To evaluate the effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the brains of persons with and without multiple sclerosis (MS) by means of postmortem histopathological examination...
- Gisslen M, Krut J, Andreasson U, Blennow K, Cinque P, Brew B, et al. Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol. 2009;9:63 pubmed publisher..These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease. ..
- Yan P, Bero A, Cirrito J, Xiao Q, Hu X, Wang Y, et al. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci. 2009;29:10706-14 pubmed publisher..Together, these findings indicate that individual amyloid plaque growth in vivo occurs over a period of weeks and may be influenced by interstitial Abeta concentration as well as reactive gliosis. ..
- Richter L, Munter L, Ness J, Hildebrand P, Dasari M, Unterreitmeier S, et al. Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Abeta and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc Natl Acad Sci U S A. 2010;107:14597-602 pubmed publisher..We conclude that these GSMs decrease Abeta42 levels by modulating APP-TMS interactions. This effect specifically emphasizes the importance of the dimeric APP-TMS as a promising drug target in Alzheimer's disease. ..