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It All Sticks Together—The APP-Related Family of Proteins and Alzheimer's

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It All Sticks Together—The APP-Related Family of Proteins and Alzheimer's Molecular Psychiatry (1999) 4, 524–528 1999 Stockton Press All rights reserved 1359–4184/99 $15.00 PROGRESS It all sticks together—the APP-related family of proteins and Alzheimer’s disease TA Bayer1, R Cappai2, CL Masters2, K Beyreuther3 and G Multhaup3 1Department of Psychiatry, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany; 2Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia; 3ZMBH, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany In the present review, we shall discuss the pros and cons of a possible functional relationship and contribution of the APP family members (APP, APLP1 and APLP2) to the development of Alzheimer’s disease: (1) APP, APLP1 and APLP2 are highly homologous proteins with similar protein domain organization. (2) All APP family proteins have been found to be aggregated in typical Alzheimer’s disease lesions. (3) Several other proteins have been implied to provide a functional link among the APP-related proteins. In normal adult brain APP, APLP1 and APLP2 are involved in synaptic processes important for memory function. We hypothesize that the functional loss of members of the APP family contributes to the gradual cognitive decline in Alzheimer’s disease patients. Keywords: APP; APLP1; APLP2 The neuropathological hallmarks of Alzheimer’s dis- gene has been located at chromosome 19q13.1 and ease (AD) include neurofibrillary tangles, neuritic pla- shown to consist of 17 exons.14 APP, APLP1 and ques, and congophilic angiopathy. While tangles are APLP2 have the structure of type I integral membrane predominantly composed of an abnormally phos- glycoproteins with a major extracellular component phorylated tau protein, ␤-amyloid has been identified and a short cytoplasmatic tail3 (Figure 1), are highly as a major component of both neuritic plaques and blood vessels with amyloid angiopathy in AD. Since the purification and characterization of cerebral amy- loid protein from senile plaques in AD and in older persons with Down syndrome,1,2 the protein compo- nents of plaques have received considerable interest. The ␤-amyloid precipitates are aggregates of 39- to 43- residues ␤A4 peptide,3,4 which originate from a larger ␤-amyloid precursor protein (APP). The discovery of amyloid precursor-like proteins related to APP classi- fies APP as a member of a multigene family.5–8 The highly homologous nature of the proteins raises the possibility of a functional relationship. Wasco et al6 isolated the human APLP2 gene, which has been assigned to chromosome 11 q23–q25.9 The mouse APLP2 promoter lacks a typical TATA box, is GC-rich, and contains several sequences for transcription factor Figure 1 The APP protein family and domain organization 10,11 binding. The mouse APLP1 genomic structure is illustrated. SP denotes the signal peptide domain; CYS the revealed 17 exons and a 5Ј region that contains puta- conserved cysteine-rich domain; Acidic the less conserved tive binding sites for AP-1, heat-shock protein, and Sp1 acidic domain; Glycosylation the N- and O-glycosylation devoid of apparent TATA and CCAAT boxes.12 Human domain; ␤A4 the ␤A4/␤-amyloid domain of APP; and TM APLP1 cDNA has been cloned recently,13 the protein indicates the transmembrane domain. The extracellular was found in human CSF suggesting that soluble domain on the aminoterminal site of the transmembrane APLP1 is released from brain cells. The human APLP1 region reveals highest divergence (arrow). The KPI domain (exon 7), OX-2 domain (exon 8) and exon 15 of APP and KPI domain (homologous to APP exon 7) and a divergent region Correspondence: TA Bayer, PhD, Department of Psychiatry, Uni- of 12 amino acids on the NH2-terminal side of the transmem- versity of Bonn Medical Center, Sigmund-Freud-Strasse 25, brane domain (12-aa exon) of APLP2 are alternatively spliced. 53105 Bonn, Germany. E-mail: bayerȰuni-bonn.de No alternative splice variants have been described for APLP1. Received 2 December 1998; revised 1 March 1999; accepted 8 Note, the ␤A4 domain is absent in APLP1 and APLP2. Not March 1999 drawn to scale. APP and Alzheimer’s disease TA Bayer et al 525 STAR Sequence alignment of the human APP superfamily. The sequences were extracted from the Swissprot data base. Alignment with Megalign (Lasergene, DNA Figure 2 Inc, Madison, WI, USA). Black boxes denote residues that match the Consensus exactly. APP and Alzheimer’s disease TA Bayer et al 526 homologous proteins (Figure 2) evolved from the com- within the first week after birth. The survivors showed mon ancestor APLP1 (Figure 3). The ␤A4/␤-amyloid deficits in balance and/or strength, but appeared heal- domain, however is unique to APP and absent in other thy up to 13 months of age.30 Recently, Rassoulzadegan members of the superfamily. APP is alternatively et al31 investigated a large APLP2 deletion in the gen- spliced (exons 7, 8 and 15), which gives rise to at least omic locus, suggesting a role of APLP2 in mitotic segre- eight isoforms expressed in a cell-type specific manner. gation of the genome and establishment of a proper APLP2 has two alternatively spliced exons, one com- nuclear structure. Increased expression of cell-associa- prises the Kunitz protease inhibitor domain encoding ted APLP2, but not APLP1, was detected in ␤A4- exon and a 12-amino acid long exon situated adjacent treated APP−/− and APP+/+ neuronal cell cultures but 15–17 to the transmembrane domain. The latter not in H2O2-treated cultures. These findings demon- resembles the tissue-specific alternative splicing of strate that ␤A4 toxicity does not require an interaction exon 15 of APP, corresponding to 18 residues and was of the ␤A4 peptide with the parental molecule (APP) first reported in leukocytes.18 APP isoforms termed L- and is therefore distinct from prion protein neurotoxic- APP that lack sequences encoded by exon 15 are modi- ity that is dependent on the expression of the parental fied by chondroitin sulfate glycosaminoglycans (CS- cellular prion protein, and that APLP2 expression may GAG), whereas the APLP2-763 isoform which contains be functionally triggered by ␤A4.32 the 12-amino acids insert is not modified by CS-GAG.19 Induction of apoptosis by trophic factor withdrawal Studies on the protein level and quantitative mRNA upregulated APP and APLP2 protein synthesis, and the analysis revealed an AD-associated increase in the pro- alternative splicing pattern of APP in neuronal PC12 portion of APP exon 7 encoded Kunitz-type serine pro- cells.33 The members of the APP gene family have been tease inhibitory-containing isoforms.20,21 The Kunitz- implicated in neuronal differentiation, since mRNA type serine protease inhibitory sequence (KPI) in the levels increased after retinoic acid induction of human APP gene diverged from its ancestral gene about 270 neuroblastoma cells (SH-SY5Y) of both APLP2 and million years ago and was inserted into the gene soon APP, whereas the increase in APLP1 mRNA expression after duplication.22 No APLP1 spliced transcripts have was significantly higher.34 Phosphorylation-dependent been discovered so far. Detailed alternative splicing regulation of APLP2 in the cytoplasmic domain by pro- patterns of APP and APLP2 have been previously tein kinase C and cdc2 kinase appears to be similar to described and reviewed by Sandbrink et al.23 that of APP. APLP1 has been shown to be phosphoryl- APLP2 is widely expressed in neural and non-neural ated by protein kinase C.35 tissues.6,24,25 In situ hybridization and quantitative The hypothesis of environmental toxins for AD has polymerase chain reaction revealed that APLP2 and received growing attention in the past years. The APP mRNA are expressed in similar, if not identical, identification of a copper (II) binding site in APP and neuronal populations and at similar levels. APLP2 APLP2 has been suggested to be involved in electron appears to mature through the same unusual transfer and radical reactions.36,37 A strong heparin- secretory/cleavage pathway as APP,8 and is found in binding site within a region conserved in rodent and post-synaptic compartments.24,26 Evidence that APP human APP, APLP1 and APLP2, was identified in the and APLP2 have a shared cellular activity besides the carbohydrate domain suggesting a role in cell KPI domain comes from the observation that recombi- adhesion.38 APP and its homologues behave as a family nant human APLP2 expressed in the yeast Pichia pas- of zinc-modulated, heparin-binding proteins.39 toris can stimulate neurite outgrowth.27 Tranfection Additionally, a conserved zinc (II) binding site was experiments of mouse APLP2 cDNA revealed that demonstrated to interact with the heparin-binding APLP2 is modified by CS-GAG at a region with little site.40 homology to APP, suggesting functional regulation, A role of APLP1 and APLP2 in AD has gained further which has been suggested to have a role in axonal interest with the discovery that both proteins are pathfinding and/or synaptogenesis in the olfactory present in typical AD-associated lesions. Crain et al25 bulb and embryonic neurons.19,28,29 APLP1 is increased showed that APLP2 antibodies label dystrophic neur- during cortical synaptic development, suggesting a role ites, a subset of plaques, neurons and reactive astro- in synaptogenesis or synaptic maturation.26 cytes in AD, which was confirmed by others.41,42 More A role in axonal pathfinding has been challenged by recently, our group reported43 that APLP1 protein also Koch et al30 who studied APLP2 knock-out mice, precipitates in a subpopulation of neuritic plaques, a which failed to show impairment of axonal outgrowth finding, which was supported recently.42 of olfactory neurons following bulbectomy. Eighty per Several proteins have been implied to provide a cent of APP and APLP2 double knock-out mice died functional link among the family of APP-related pro- Figure 3 Phylogenetic tree of APP, APLP1 and APLP2 and ancestral relationships between sequences.
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