| Structural highlights
Disease
[A4_HUMAN] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:104300]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:605714]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.[27] [28] [29] [30] [31]
Function
[A4_HUMAN] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.[32] [33] [34] [35] [36] Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.[37] [38] [39] [40] [41] Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).[42] [43] [44] [45] [46] The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.[47] [48] [49] [50] [51] N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).[52] [53] [54] [55] [56]
Publication Abstract from PubMed
Alzheimer disease is associated with deposition of the amyloidogenic peptide Abeta in the brain. Passive immunization using Abeta-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified Abeta species (AbetapE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize AbetapE3 with affinities of 1-10 nm and inhibit AbetapE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in AbetapE3 oligomer-treated mice. Crystal structures of Fab-AbetapE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the AbetapE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.
Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy.,Piechotta A, Parthier C, Kleinschmidt M, Gnoth K, Pillot T, Lues I, Demuth HU, Schilling S, Rahfeld JU, Stubbs MT J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub , 2017 Jun 16. PMID:28623233[57]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Liepnieks JJ, Ghetti B, Farlow M, Roses AD, Benson MD. Characterization of amyloid fibril beta-peptide in familial Alzheimer's disease with APP717 mutations. Biochem Biophys Res Commun. 1993 Dec 15;197(2):386-92. PMID:8267572
- ↑ Farlow M, Murrell J, Ghetti B, Unverzagt F, Zeldenrust S, Benson M. Clinical characteristics in a kindred with early-onset Alzheimer's disease and their linkage to a G-->T change at position 2149 of the amyloid precursor protein gene. Neurology. 1994 Jan;44(1):105-11. PMID:8290042
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- ↑ Pasalar P, Najmabadi H, Noorian AR, Moghimi B, Jannati A, Soltanzadeh A, Krefft T, Crook R, Hardy J. An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). Neurology. 2002 May 28;58(10):1574-5. PMID:12034808
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- ↑ Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. PMID:15668448 doi:64/2/377
- ↑ Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J. Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 2000 Sep 1;275(35):27110-6. PMID:10821838 doi:10.1074/jbc.M003154200
- ↑ Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124-6. PMID:2111584
- ↑ Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001 Jun;49(6):697-705. PMID:11409420
- ↑ Greenberg SM, Shin Y, Grabowski TJ, Cooper GE, Rebeck GW, Iglesias S, Chapon F, Tournier-Lasserve E, Baron JC. Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology. 2003 Mar 25;60(6):1020-2. PMID:12654973
- ↑ Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S, Arbustini E, Palladini G, Diegoli M, Genovese E, Ferrari G, Coverlizza S, Merlini G. A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005 Oct;58(4):639-44. PMID:16178030 doi:10.1002/ana.20571
- ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
- ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
- ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
- ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
- ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
- ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
- ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
- ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
- ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
- ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
- ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
- ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
- ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
- ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
- ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
- ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
- ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
- ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
- ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
- ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
- ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
- ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
- ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
- ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
- ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
- ↑ Piechotta A, Parthier C, Kleinschmidt M, Gnoth K, Pillot T, Lues I, Demuth HU, Schilling S, Rahfeld JU, Stubbs MT. Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy. J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub , 2017 Jun 16. PMID:28623233 doi:http://dx.doi.org/10.1074/jbc.M117.777839
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