Expression of the APP Gene Family in Brain Cells, Brain Development and Aging

Sandbrink, Rupert; Mönning, Ursula; Masters, Colin L.; Beyreuther, Konrad

doi:10.1159/000213840

Cited by 22 publications

(16 citation statements)

References 19 publications

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“…By this means, APP could be coimmunoprecipitated from WT and APLP2−/−, but not from APP−/− and APLP1−/− brain samples (Figure 6A), showing specific heterointeraction of APP and APLP1 in vivo . In mouse brain, at least three distinct forms of APP with molecular weights of 100, 108, and 120 kDa were detected (Figure 6A; as indicated), likely representing different post‐translationally modified APP695 species (Sandbrink et al , 1997). Interestingly, only the mature, high‐molecular‐weight forms of APP with molecular weights of 108 and 120 kDa were coimmunoprecipitated with APLP1 (Figure 6A), suggesting that a particular pool of APP exists in complex with APLP1 in vivo .…”

Section: Resultsmentioning

confidence: 91%

Homo- and heterodimerization of APP family members promotes intercellular adhesion

Soba

Eggert

Wagner

et al. 2005

EMBO J

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273

344

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The amyloid precursor protein (APP) plays a central role in Alzheimer's disease, but its physiological function and that of its mammalian paralogs, the amyloid precursor-like proteins 1 and 2 (APLPs), is still poorly understood. APP has been proposed to form dimers, a process that could promote cell adhesion via trans-dimerization. We investigated the dimerization and cell adhesion properties of APP/APLPs and provide evidence that all three paralogs are capable of forming homo-and heterocomplexes. Moreover, we show that trans-interaction of APP family proteins promotes cell-cell adhesion in a homo-and heterotypic fashion and that endogenous APLP2 is required for cell-cell adhesion in mouse embryonic fibroblasts. We further demonstrate interaction of all the three APP family members in mouse brain, genetic interdependence, and molecular interaction of APP and APLPs in synaptically enriched membrane compartments. Together, our results provide evidence that homo-and heterocomplexes of APP/APLPs promote trans-cellular adhesion in vivo.

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Section: Resultsmentioning

confidence: 91%

Homo- and heterodimerization of APP family members promotes intercellular adhesion

Soba

Eggert

Wagner

et al. 2005

EMBO J

Self Cite

273

344

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“…APP is ubiquitously expressed in mammalian cells with a broad tissue distribution. The APP splice variant containing 695 amino acids is expressed at higher levels in neurons, whereas the 751‐ and the 770‐residues isoforms are widely expressed in non‐neuronal cells but also occur in neurons 5–7 . All three isoforms are potentially amyloidogenic, since they share the same Abeta, transmembrane, and intracellular domains.…”

Section: Introductionmentioning

confidence: 99%

Altered Subcellular Distribution of the Alzheimer's Amyloid Precursor Protein Under Stress Conditions

Domingues

Henriques

et al. 2007

Annals of the New York Academy of Sciences

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Altered metabolism of the Alzheimer's amyloid precursor protein (APP) appears to be a key event in the pathogenesis of Alzheimer's disease (AD), and both altered phosphorylation and oxidative stress appear to affect the production of the toxic Abeta fragment. Our results show that altered processing of APP was observed under conditions of stress induced by sodium azide in the presence of 2-deoxy-D-glucose (2DG). As previously reported, the production of the secreted fragment of APP (sAPP) was inhibited. Using APP-GFP fusion proteins, we show that 2DG causes the accumulation/delay of APP in the endoplasmic reticulum (ER)/Golgi (G). The 751 isoform accumulated preferentially in the G, whereas the 695 isoform was blocked preferentially at the ER. This effect was augmented in the presence of sodium azide. APP subcellular distribution was also affected at the plasma membrane. The involvement of protein phosphorylation in APP subcellular localization was reinforced by the effect of drugs, such as phorbol 12-myristate 13-acetate (PMA), since APP was completely depleted from the membrane in the presence of 2DG and PMA. Thus, the hypothesis that APP is processed in a phosphorylation-dependent manner and that this may be of clinical relevance appears to hold true even under stress conditions. Our results provide evidence for a role of protein phosphorylation in APP sorting under stress conditions and contribute to the understanding of the molecular basis of AD.

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“…22 No APLP1 spliced transcripts have been discovered so far. Detailed alternative splicing patterns of APP and APLP2 have been previously described and reviewed by Sandbrink et al 23 APLP2 is widely expressed in neural and non-neural tissues. 6,24,25 In situ hybridization and quantitative polymerase chain reaction revealed that APLP2 and APP mRNA are expressed in similar, if not identical, neuronal populations and at similar levels.…”

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confidence: 99%

It all sticks together—the APP-related family of proteins and Alzheimer's disease

et al. 1999

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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; APLP2The neuropathological hallmarks of Alzheimer's disease (AD) include neurofibrillary tangles, neuritic plaques, and congophilic angiopathy. While tangles are predominantly composed of an abnormally phosphorylated tau protein, ␤-amyloid has been identified as a major component of both neuritic plaques and blood vessels with amyloid angiopathy in AD. Since the purification and characterization of cerebral amyloid protein from senile plaques in AD and in older persons with Down syndrome, 1,2 the protein components 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 classifies APP as a member of a multigene family. [5][6][7][8] The highly homologous nature of the proteins raises the possibility of a functional relationship. Wasco et al 6 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 binding. 10,11 The mouse APLP1 genomic structure revealed 17 exons and a 5Ј region that contains putative binding sites for AP-1, heat-shock protein, and Sp1 devoid of apparent TATA and CCAAT boxes. 12 Human APLP1 cDNA has been cloned recently, 13 gene has been located at chromosome 19q13.1 and shown to consist of 17 exons. 14 APP, APLP1 and APLP2 have the structure of type I integral membrane glycoproteins with a major extracellular component and a short cytoplasmatic tail 3 (Figure 1), are highly Figure 1 The APP protein family and domain organization is illustrated. SP denotes the signal peptide domain; CYS the conserved cysteine-rich domain; Acidic the less conserved acidic domain; Glycosylation the N-and O-glycosylation domain; ␤A4 the ␤A4/␤-amyloid domain of APP; and TM indicates the transmembrane domain. The extracellular domain on the aminoterminal site of the transmembrane 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 of 12 amino acids on the NH 2 -terminal side of the tra...

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Expression of the APP Gene Family in Brain Cells, Brain Development and Aging

Cited by 22 publications

References 19 publications

Homo- and heterodimerization of APP family members promotes intercellular adhesion

Homo- and heterodimerization of APP family members promotes intercellular adhesion

Altered Subcellular Distribution of the Alzheimer's Amyloid Precursor Protein Under Stress Conditions

It all sticks together—the APP-related family of proteins and Alzheimer's disease

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