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physiological functions of the amyloid precursor protein family

Amyloid precursor protein (APP) gives rise to the amyloid 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 cartier gold engagement imitation rings 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.

a The schematic shows the canonical amyloid precursor protein (APP) processing pathways. Processing by along the non amyloidogenic pathway (green background) occurs in the amyloid (A region (shown in red), liberates APPs ( APP ectodomain fragment) and generates p3. By contrast, processing along the amyloidogenic pathway (red background) generates A (through and cleavage) and liberates APPs An intracellular fragment (APP intracellular domain (AICD)) is released in both pathways. The positions of cleavage sites are indicated. b The schematic shows the non canonical APP processing. Cleavage by produces three soluble APPs fragments and C terminal fragment (CTF which is further processed by and (top left panel). Cleavage by meprin at three sites gives rise to three soluble fragments (top right panel). Caspases cleave within the intracellular domain to yield C31 and, after subsequent cleavage, Jcasp (lower right panel). c The schematic shows A and N terminal cleavage sites. APP processing sites are indicated; the numbers denote C terminal residues of full length APP695. The top panel indicates the sites of canonical secretases, with residues numbered relative to the A N terminus. The bottom panels shows the sites of non canonical processing. ADAM10, disintegrin and metalloproteinase domain containing protein 10; APH1, anterior pharynx defective 1; NCT, nicastrin; PEN2, presenilin enhancer 2; PS1, presenilin 1.

a The schematic shows interactions within the amyloid precursor protein (APP) family (cis or trans). The formation of trans dimers (1) and cis dimers (2) can occur in a homophilic manner (for example, APP and APP) or in a heterophilic manner (for example, APP and an APP like protein (APLP)56, 59). Secreted APPs ( generated APP ectodomain fragment) binds to transmembrane APP as an autocrine or a paracrine ligand62 (3). b Other APP trans interactors act as receptors for APP or its fragments. For example, membrane bound APP (4) can bind to cell surface proteins such as death receptor 6 (DR6) on neighbouring cells to induce signalling in these cells86. APPs binds as a ligand to as yet unknown cell surface receptors (5). Other secreted APP fragments (6), including A may function as ligands, but only receptors for amyloid (A have so far been elucidated. c Other APP cis interactors can show receptor like cis signalling. For example, DR6 (7) can interact on the axonal membrane to induce caspases via its DR domain82, 84. In addition, specific membrane proteins (such as low density lipoprotein receptor (LDLR) family members) bind to APP, modulating its subcellular targeting, processing and internalization. APP may function as a receptor like molecule (8) that binds to specific ligands (for example, pancortins)113. APP and C terminal fragments (CTFs) can induce signals via adaptors and can be further processed to liberate APP intracellular domain (AICD) to regulate transcription. Larger complexes of membrane proteins (9) can interact cartier ring copy online with APP as a co receptor (for example, together with contactin 4 (Ref. 81)). d Selected interaction partners of APP are shown. APP interacts with several proteins through its extracellular portion (top) and its intracellular domain (bottom). Known interactors with mapped APP binding motifs are shown in the same colour as their interacting APP domains. Extracellular and intracellular interactors with non mapped interaction sites are listed underneath. The LDLR family members have been reported to interact both extracellularly and intracellularly with APP (involving FE65 as an adaptor). The APP NMDA receptor (NMDAR) interacting domain has not yet been mapped. The bottom panel lists binding proteins in the same colour as their interaction motifs, indicated by brackets or with bold within the AICD sequence. Some of the interactors (for example, FE65, X11 (also known as MINT) and NUMB) are adaptor proteins that link APP to other proteins (listed in pale yellow boxes on the far right). See Supplementary information S1 (table) for protein functions, protein abbreviations of indirect interactors (binding to C terminal adaptors) and references. AcD, acidic domain; ARH, autosomal recessive hypercholesterolaemia protein; BRI2, brichos domain containing 2; CHT, high affinity choline transporter; COL1, collagen type 1; CPEB, cytoplasmic polyadenylation element binding protein; CRBN, protein cerebron; DAB1, disabled homologue 1; DISC1, disrupted in schizophrenia 1 protein; FBLN1, fibulin 1; FKBP12, FK506 binding protein 12; FLOT1, flotilin 1; GABABR, GABA type B receptor; GPC1, glypican 1; GRB2, growth factor receptor bound protein 2; JIP, JUN N terminal kinase interacting protein; LINGO1, leucine rich repeat and Ig domain containing Nogo receptor interacting protein 1; LRP1, LDLR related protein 1; MED12, Mediator complex subunit 12; NOGOR, Nogo 66 receptor; NTN1, netrin 1; OLFM1, olfactomedin 1; P75NTR, low affinity neurotrophin receptor p75; PAT1, protein interacting with APP tail 1; PIN1, peptidyl prolyl cis isomerase NIMA interacting 1; RELN, reelin; SHC, SRC homology 2 domain containing transforming protein 1; SNX17, sorting nexin 17; SPON1, F spondin; SORL1, sortilin related receptor; SORT1, sortilin 1; SP, signal peptide; STUB1, STIP1 homology and U box containing protein 1; SYT1, synaptotagmin 1; SYP, synaptophysin; TAG1, transient axonal glycoprotein 1 (also known as contactin 2); TFCP2, transcription factor CP2 (also known as LBP2/CP2/LSF); TRKA, tyrosine kinase receptor A; VAMP2, vesicle associated membrane protein 2.

Different variants of amyloid precursor protein (APP) are cartier fake gold love ring expressed in knock in (KI) models. Most APP variants contain mouse amyloid (A (mA red). In the so called APP/hA variant, the mouse A region was replaced by the human A sequence (hA red) with simultaneous introduction of the Swedish (Swe), London (Lon) and Arctic (Arc) mutations, which are linked to familial Alzheimer disease (FAD). Owing to a frame shift (FS), the carboxyl terminus is truncated (mutC)123. and indicate secretase cleavage sites. The dashed lines show the location of the membrane, and the intracellular T668 residue and YENPTY motif are indicated. The numbering of the residues is based on APP695. Wild type APP is shown in part a. Some mutants, shown in part b, have been generated that express exclusively extracellular fragments. APP ectodomain fragment (APPs mice contain a stop codon behind the site71, 91. APPs mice express APP residues up to the site, followed by a flag tag (blue)126. Right (parts b,c): the viability of single gene KI mice (left) or of double mutants (right) generated by crossing APP KI mice onto a constitutive Aplp2 background is indicated. Some mutants (part c) express APP with intracellular truncations. APP mice lack the last 15 residues (dashed box)91, 122. In APP/hA mice, a FS was introduced at position H657 that results in 10 additional mutant residues (blue box). The A region was humanized and contains the Swe (K595N how much is cartier love ring fake Arc (E618G) and Lon (V642I) FAD mutations123. The numbering of the residues is based on APP695.

Heber, S. et al. Mice with combined gene knock outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. in Molecular Biology at Ludwig Maximillians University, Munich, Germany. After postdoctoral research periods at Manchester University, UK, and Zurich University, Switzerland, she joined the Max Planck Institute for Brain Research, Frankfurt, Germany, as a junior group leader. In 2004, she was appointed Professor for Functional Genomics at Heidelberg University, Germany. Her research focuses on the molecular mechanisms of synaptic transmission disorders and the pathogenesis of neurodegenerative diseases, particularly Alzheimer disease. Her laboratory has generated a variety of knockout, knock in and conditional mouse mutants to dissect the functions of amyloid precursor protein (APP) and the related APP like proteins (APLPs) in nervous system development and the adult CNS. Ulrike C. M homepage

Contact Ulrike C. He became Director of the Institute of Clinical Neuroanatomy in 2005. His research focuses on the structural and functional plasticity of neurons in the hippocampus. His group uses in vivo and in vitro models to study the mechanistic role of amyloid precursor protein (APP) and other molecules in the context of learning and memory, brain injury and Alzheimer disease. work at the Max Planck Institute (MPI) of Neurobiology, Martinsried, Germany. He subsequently became a group leader with Janssen Cilag, Neuss, Germany, and afterwards a junior group leader at the MPI of Neurobiology, Martinsried, Germany. In 2004, he became a professor and institute director of the Zoological Institute at the TU Braunschweig, Germany. He has been co affiliated with the Helmholtz Center for Infectious Research, Braunschweig, Germany, since 2012. His research includes the cellular mechanism of learning, memory and forgetting, the physiological function of amyloid precursor protein (APP) and its fragments, neuroinflammation and neurodegeneration. Martin Korte homepage
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