Disease relevance of APLP2

• Our results demonstrate species (i.e., genetic) differences in the response to TD-induced damage and support a role for APP and APLP2 in the response to brain injury [1].
• Our results suggest that even though APLP1 and APLP2 cannot generate Abeta, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31 [2].
• These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders [3].
• In this paper we show that APLP1 and APLP2 mRNA expression is upregulated during RA-induced differentiation of human SH-SY5Y neuroblastoma cells [4].
• Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease [5].

Psychiatry related information on APLP2

• These data uncover a novel biological function for APP and APLP2 in copper efflux and provide a new conceptual framework for the formerly diverging theories of copper supplementation and chelation in the treatment of Alzheimer's disease [6].
• The aetiology and pathogenesis of this progressive dementia is poorly understood, but symptomatic disease is associated histopathologically with amyloid plaques, neurofibrillary tangles and neuronal loss primarily in the temporal lobe and neocortex of the brain [7].
• We previously showed that mice over-expressing a human mutated form of APP (APP(V717F)) display age-dependent recognition memory deficits associated with the progression of amyloid deposition [8].
• Plasma levels of amyloid beta 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome [9].

High impact information on APLP2

• C reactive protein, the first innate immunity receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver [10].
• In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes [11].
• Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins [12].
• Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA [13].
• APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy [13].

Chemical compound and disease context of APLP2

• These findings suggest that nicotine treatment facilitates the increase in the expression of mRNA and protein of the APP and APLP2 genes in rat brain and SH-SY5Y neuroblastoma cells [14].
• Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction [15].
• Increased gene expression of beta-amyloid precursor protein and its homologues APLP1 and APLP2 in human neuroblastoma cells in response to retinoic acid [4].
• Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease [6].
• The amyloid beta protein (beta/A4) that is deposited in senile plaques and in cerebral vessels in Alzheimer's disease (AD) is derived from a larger membrane-associated glycoprotein, the amyloid beta protein precursor (APP) [16].

Biological context of APLP2

• The rapid kinetics for turnover of APP and APLP2 predict a sensitive balance of synthesis, transport, and elimination rates that may be critical to normal neuronal functions and metabolic fates of these proteins [17].
• Serotonin also stimulated the release of the APLP2 ectodomain, suggesting that additional members of the APP multigene family are processed via similar regulated pathways [18].
• A minimal region that includes sequences 99 bp upstream of the predominant transcription start site of the APLP2 promoter was sufficient to direct high levels of CAT expression [19].
• The APLP2 promoter lacks a typical TATA box, is GC-rich, and contains several sequences for transcription factor binding [19].
• Here we report on the expression of APP and its homologue, the amyloid precursor like protein 2 (APLP2), during cutaneous wound repair using a full-thickness excisional wound healing model in mice [20].

Anatomical context of APLP2

• 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 [21].
• In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion [1].
• We report that in stably transfected Chinese hamster ovary and transiently transfected African green monkey kidney (COS-1) cells, APLP2 is modified by glycosaminoglycan (GAG) addition [22].
• Overexpression of BACE in cultured cells led to increased APLP2 processing [23].
• Immunocytochemically, all proliferation competent keratinocytes of the normal as well as the wound site epidermis showed increased expression of APP but not of APLP2 [20].

Associations of APLP2 with chemical compounds

• Presynaptic APP and APLP2 are sialylated and N- and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan and/or dermatan sulfate glycosaminoglycan [17].
• Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site [22].
• Contained within this heterologous region is a predicted CS modification site, ENEGSGMAEQ (APLP2 residues 610-619); APLP2 polypeptides harboring a serine-to-alanine substitution at position 614 fail to undergo CS GAG modification [22].
• We suggest that CS GAG modification of a subset of APP and APLP2 isoforms represents a means of generating functional diversity for these polypeptides [24].
• Analysis of APLP2 expression revealed regulated alternative splicing of the Kunitz protease inhibitor domain (KPI, homologous to exon 7 of APP) and a non-homologous insert of 12 amino acids on the NH2-terminal side of the transmembrane domain [25].

Physical interactions of APLP2

• Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain [26].
• Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains [27].
• Fe65 and X11beta co-localize with and compete for binding to the amyloid precursor protein [28].
• Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity [29].
• Like APP, APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o) indicating that it may be an additional cell surface activator of this G protein [30].

Enzymatic interactions of APLP2

• Alternatively, APP can be cleaved within the amyloid beta domain by alpha-secretase releasing the non-amyloidogenic product sAPP alpha, which has been shown to have neuroprotective properties [31].
• ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site [32].
• Gelatinase A possesses a beta-secretase-like activity in cleaving the amyloid protein precursor of Alzheimer's disease [33].
• The first route involves a protease known as "APP secretase," which cleaves within the amyloid sequence, thereby mitigating amyloid formation [34].
• The novel transmembrane aspartic protease BACE (for Beta-site APP Cleaving Enzyme) is the beta-secretase that cleaves amyloid precursor protein to initiate beta-amyloid formation [35].

Co-localisations of APLP2

• More importantly, this APP immunoreactivity colocalized with angiopathic amyloid, which is characterized by phenol-resistant, birefringent congophilia [36].
• Type I familial amyloid polyneuropathy (FAP) is one form of systemic amyloidosis in which ApoE co-localizes with amyloid deposits [37].
• In AD brains, levels of HSP90 were increased in both the cytosolic and membranous fractions, and HSP90 was colocalized with amyloid plaques [38].
• ApoAI and TTR co-localized in amyloid deposits as demonstrated by immunohistochemistry [39].
• The serine protease inhibitor alpha 1-antichymotrypsin (ACT) consistently colocalizes with amyloid deposits of Alzheimer's disease (AD) and may contribute to the generation of amyloid proteins and/or physically affect fibril assembly [40].

Regulatory relationships of APLP2

• Amyloid beta up-regulates brain-derived neurotrophic factor production from astrocytes: rescue from amyloid beta-related neuritic degeneration [41].
• Apolipoprotein E genotype regulates amyloid-beta cytotoxicity [42].
• RESULTS: ASP-2 expressed in HEK293-cells cleaved the Swedish mutant amyloid precursor at different beta-sites at different pHs in vitro [43].
• APLP2 had neurite outgrowth-promoting activity similar to that of the APP isoforms [44].
• Epidermal growth factor (EGF) also induced APLP2 accumulation in culture medium [45].

Other interactions of APLP2

• Immunocytochemical studies of brain tissue from 26 patients with Down's syndrome showed that the deposition of A4 protein amyloid began in these patients approximately 50 years earlier than it began in 127 normal aging subjects studied previously, although the rate of deposition was the same [5].
• Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE [46].
• Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease [47].
• BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein [48].
• Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein [49].

Analytical, diagnostic and therapeutic context of APLP2

• APP-immunoreactive bands detected in western blots of cellular protein extracts were only detected by anti-APP antibodies to peptides with strong homology to APLP2, suggesting that these bands represent APP-like proteins and not APP itself [50].
• APLP2 was constitutively shed and released into culture medium in SV40-immortalized human corneal epithelial cells as assessed by Western blotting, flow cytometry, and indirect immunofluorescence [45].
• The human APLP2 ectodomain (sAPLP2) was expressed in the yeast Pichia pastoris and the recombinant sAPLP2 was purified from the culture medium in a single step by metal-chelating Sepharose chromatography [44].
• APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein [3].
• Immunohistochemistry reveals staining for both APLP1 and APLP2 in neurons and blood vessels in AD and control cases [51].

References