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

Abstract

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...

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

“…APP is cleaved by secretases, resulting in several fragments, including the Ab-peptide in Alzheimer's disease. 10 An increase in the generation of Ab is, according to the amyloid hypothesis of Alzheimer's disease, the trigger for disease pathogenesis. 11 Ab has been implicated in multiple functions, particularly in cytotoxicity of its oligomeric forms, 12,13 although their functional roles are not fully understood.…”

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

“…ilarity in the amino acid sequence, APLP2 is the closest homologue to APP (73). Because APP and APLP2 are highly homologous proteins with similar protein domain organization in peripheral tissue (73), it is of interest that VPA specifically down-regulated APP and did not affect APLP2 levels.…”

“…Because APP and APLP2 are highly homologous proteins with similar protein domain organization in peripheral tissue (73), it is of interest that VPA specifically down-regulated APP and did not affect APLP2 levels. As expected, the levels of soluble APLP2 (sAPLP2␣) were not changed(datanotshown).Therefore,wesuggestthattheHDACdependent APP down-regulation underlies a highly specific mechanism.…”

JNK-interacting protein-1 promotes transcription of Aβ protein precursor but not Aβ precursor-like proteins, mechanistically different than Fe65

“…A␤PP is part of a larger gene family that includes amyloid ␤ precursor-like protein-1 (APLP1) and APLP2 (16). Research has been focused on A␤PP itself because mutations in it are linked to familial AD, and it is the precursor from which the A␤ peptide is derived (1, 2); however, much less is known about the APLPs.…”