Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains

McNamara, Megan J.; Ruff, Christian T.; Wasco, Wilma; Tanzi, Rudolph E.; Wang, Shuai; Hyman, Bradley T.

doi:10.1016/s0006-8993(98)00653-2

Cited by 38 publications

(31 citation statements)

References 17 publications

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“…Crain et al 25 showed that APLP2 antibodies label dystrophic neurites, a subset of plaques, neurons and reactive astrocytes in AD, which was confirmed by others. 41,42 More recently, our group reported 43 that APLP1 protein also precipitates in a subpopulation of neuritic plaques, a finding, which was supported recently. 42 Several proteins have been implied to provide a functional link among the family of APP-related pro-teins.…”

supporting

confidence: 55%

“…41,42 More recently, our group reported 43 that APLP1 protein also precipitates in a subpopulation of neuritic plaques, a finding, which was supported recently. 42 Several proteins have been implied to provide a functional link among the family of APP-related pro-teins. Duilio et al 44 reported that Fe65 and another Fe65-like protein (Fe65L2) interact with APP, APLP1 and APLP2.…”

supporting

confidence: 55%

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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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supporting

confidence: 55%

supporting

confidence: 55%

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

et al. 1999

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“…It is interesting to note that APLP1 may also be involved in Alzheimer's disease. Accumulation of APLP1 has been found in the senile plaques and in aged brains (Bayer et al, 1997;McNamara et al, 1998). Based on our results, we suggest that induction of APLP1 expression by p53, which responds to some intrinsic stress in brain, may further enhance neuronal apoptosis and augments neurodegeneration.…”

Section: Discussionsupporting

confidence: 65%

“…Modulation of APLP1 protein expression affects the neuroblastoma cell death upon stress. Importantly, APLP1 expression is associated with Alzheimer's disorders (McNamara et al, 1998;Bayer et al, 1999). Such a functional relationship between p53 and APLP1 might shed light on the pathogenesis of these disorders.…”

Section: Discussionmentioning

confidence: 97%

“…Knockout mice studies have revealed that the functions of APP and its two paralogues are redundant (Heber et al, 2000). Indeed, both APLP1 and APLP2 have been found to accumulate in the senile plaques of Alzheimer's patients' brains (Bayer et al, 1997;McNamara et al, 1998). The specific contribution of APLP1 and APLP2 to the pathogenesis of Alzheimer's remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress

et al. 2007

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The tumor suppressor p53 is a key modulator of the cellular stress response, inducing cell-cycle arrest, apoptosis, senescence and cell differentiation. To evaluate further the molecular mechanism underlying p53 function, the transcriptional profiles of proliferating and senescent WI-38 cells, both wild-type p53 expressers and counterparts with an inactivated p53, were compared by DNA microarray analysis. In particular, the amyloid-b precursor-like protein 1 (APLP1) is induced in senescent cells in a p53-dependent manner. APLP1 was confirmed to be a novel transcriptional target of p53 by in vivo and in vitro characterization of a p53 responsive element found in the first intron of the APLP1 gene locus. APLP1 knockdown experiments demonstrate that APLP1 is required for the proliferation of fibroblastic and epithelial cells. Moreover, depletion of APLP1 expression diminishes stress-induced apoptosis of neural cells, whereas ectopic APLP1 expression augments apoptosis. Based on these data, a mechanism is proposed whereby p53-dependent induction of APLP1 is involved in neural cell death, and which may exacerbate neuronal cell loss in some acute or chronic neurodegenerative disorders.

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Deletion of the amyloid precursor‐like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus

Vnencak

Paul

Hick

et al. 2015

J of Comparative Neurology

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Amyloid precursor-like protein 1 (APLP1) is a transmembrane synaptic protein belonging to the amyloid precursor protein (APP) gene family. Although the role of this gene family-in particular of APP-has been intensely studied in the context of Alzheimer's disease, the physiological roles of its family members remain poorly understood. In particular, the function of APLP1, which is predominantly expressed in the nervous system, has remained enigmatic. Since APP has been implicated in synaptic plasticity, we wondered whether APLP1 could play a similar role. First, using in situ hybridization and laser microdissection combined with reverse transcription-quantitative polymerase chain reaction (PCR) we observed that Aplp1 mRNA is highly expressed in dentate granule cells. Having this examined, we studied synaptic plasticity at the perforant path-granule cell synapses in the dentate gyrus of APLP1-deficient mice in vivo. Analysis of field excitatory postsynaptic potentials evoked by stimulation of perforant path fibers revealed increased excitatory transmission in APLP1-deficient mice. Moreover, we observed decreased paired-pulse inhibition of population spikes indicating a decrease in network inhibition upon deletion of APLP1. In contrast, short-term presynaptic plasticity (STP) as well as long-term synaptic plasticity (LTP) was unchanged in the absence of APLP1. Based on these results we conclude that APLP1 deficiency on its own does not lead to defects in synaptic plasticity, but affects synaptic transmission and network inhibition in the dentate gyrus.

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Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains

Cited by 38 publications

References 17 publications

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

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

Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress

Deletion of the amyloid precursor‐like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus

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