Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease.

ABSTRACT: Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the Abeta42 peptide from the beta-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of Abeta42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in Abeta42 secretion and identified leucine-rich repeat transmembrane 3 (LRRTM3) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of Abeta40, Abeta42, and sAPPbeta, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases Abeta secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma Abeta42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.

SUBMITTER: Majercak J

PROVIDER: S-EPMC1635650 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).

Project description:Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within ?-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid ? (A?) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted A?, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ?400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5'UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p?=?0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p?=?0.02-0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.

| S-EPMC3672107 | biostudies-literature

Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer's disease.

Project description:Beta-secretase (BACE1) is a key enzyme in the formation of amyloid-?; its activity/concentration is increased in brain and cerebrospinal fluid of patients with late-onset Alzheimer's disease (LOAD). Since BACE1 was found also in blood, we evaluated its potential as peripheral biomarker. To this aim, serum BACE1 activity was assessed in 115 subjects with LOAD and 151 controls. We found that BACE1 changed across groups (p < 0.001) with a 25% increase in LOAD versus controls. High levels of BACE1 (IV quartile) were independently associated with the diagnosis of LOAD (OR 2.8; 1.4-5.7). Diagnostic accuracy was 76% for LOAD. Our data suggest that increased BACE1 activity in serum may represent a potential biomarker for LOAD. Additional studies are needed to confirm the usefulness of BACE1, alone or in combination with other markers, in discriminating patients and predicting LOAD onset and progression.

| S-EPMC7031490 | biostudies-literature

Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation.

Project description:Accumulation of the amyloid beta (Abeta) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer disease. We previously demonstrated that the C-terminal 37 amino acids of lipoprotein receptor-related protein (LRP) robustly promoted Abeta generation independent of FE65 and specifically interacted with Ran-binding protein 9 (RanBP9). In this study we found that RanBP9 strongly increased BACE1 cleavage of APP and Abeta generation. This pro-amyloidogenic activity of RanBP9 did not depend on the KPI domain or the Swedish APP mutation. In cells expressing wild type APP, RanBP9 reduced cell surface APP and accelerated APP internalization, consistent with enhanced beta-secretase processing in the endocytic pathway. The N-terminal half of RanBP9 containing SPRY-LisH domains not only interacted with LRP but also with APP and BACE1. Overexpression of RanBP9 resulted in the enhancement of APP interactions with LRP and BACE1 and increased lipid raft association of APP. Importantly, knockdown of endogenous RanBP9 significantly reduced Abeta generation in Chinese hamster ovary cells and in primary neurons, demonstrating its physiological role in BACE1 cleavage of APP. These findings not only implicate RanBP9 as a novel and potent regulator of APP processing but also as a potential therapeutic target for Alzheimer disease.

| S-EPMC2673255 | biostudies-literature

Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer's disease amyloid precursor protein.

Project description:BACE1 is responsible for ?-secretase cleavage of the amyloid precursor protein (APP), which represents the first step in the production of amyloid ? (A?) peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of patients with Alzheimer's disease (AD). The association between oxidative stress (OS) and AD has prompted investigations that support the potentiation of BACE1 expression and enzymatic activity by OS. Here, we have established conditions to analyse the effects of mild, non-lethal OS on BACE1 in primary neuronal cultures, independently from apoptotic mechanisms that were shown to impair BACE1 turnover. Six-hour treatment of mouse primary cortical cells with 10-40 µM hydrogen peroxide did not significantly compromise cell viability but it did produce mild oxidative stress (mOS), as shown by the increased levels of reactive radical species and activation of p38 stress kinase. The endogenous levels of BACE1 mRNA and protein were not significantly altered in these conditions, whereas a toxic H2O2 concentration (100 µM) caused an increase in BACE1 protein levels. Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, ?-CTF. Subcellular fractionation techniques showed that mOS caused a major rearrangement of BACE1 localization from light to denser fractions, resulting in an increased distribution of BACE1 in fractions containing APP and markers for trans-Golgi network and early endosomes. Collectively, these data demonstrate that mOS does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis.

| S-EPMC3629182 | biostudies-literature

Novel Anti-Alzheimer's Therapeutic Molecules Targeting Amyloid Precursor Protein Processing.

Project description:Alzheimer's disease (AD) is the most common cause of dementia among older people, and the prevalence of this disease is estimated to rise quickly in the upcoming years. Unfortunately, almost all of the drug candidates tested for AD until now have failed to exhibit any efficacy. Henceforth, there is an increased necessity to avert and/or slow down the advancement of AD. It is known that one of the major pathological characteristics of AD is the presence of senile plaques (SPs) in the brain. These SPs are composed of aggregated amyloid beta (A?), derived from the amyloid precursor protein (APP). Pharmaceutical companies have conducted a number of studies in order to identify safe and effective anti-A? drugs to combat AD. It is known that ?-, ?-, and ?-secretases are the three proteases that are involved in APP processing. Furthermore, there is a growing interest in these proteases, as they have a contribution to the modulation and production of A?. It has been observed that small compounds can be used to target these important proteases. Indeed, these compounds must satisfy the common strict requirements of a drug candidate targeted for brain penetration and selectivity toward different proteases. In this article, we have focused on the auspicious molecules which are under development for targeting APP-processing enzymes. We have also presented several anti-AD molecules targeting A? accumulation and phosphorylation signaling in APP processing. This review highlights the structure-activity relationship and other physicochemical features of several pharmacological candidates in order to successfully develop new anti-AD drugs.

| S-EPMC7206886 | biostudies-literature

The amyloid precursor protein locus and very-late-onset Alzheimer disease.

Project description:Although mutations in the amyloid-beta precursor protein (APP) gene are known to confer high risk of Alzheimer disease (AD) to a small percentage of families in which it has early onset, convincing evidence of a major role for the APP locus in late-onset AD has not been forthcoming. In this report, we have used a covariate-based affected-sib-pair linkage method to analyze the chromosome 21 clinical and genetic data obtained on affected sibships by the National Institute of Mental Health Alzheimer Disease Genetics Initiative. The baseline model (without covariates) gave a LOD score of 0.02, which increases to 1.43 when covariates representing the additive effects of E2 and E4 are added. Larger increases in LOD scores were found when age at last examination/death (LOD score 5.54; P=.000002) or age at onset plus disease duration (LOD score 5.63; P=.000006) were included in the linkage model. We conclude that the APP locus may predispose to AD in the very elderly.

| S-EPMC1226076 | biostudies-literature

Adaptor protein 2-mediated endocytosis of the ?-secretase BACE1 is dispensable for amyloid precursor protein processing.

Project description:The ?-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER-Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

| S-EPMC3374752 | biostudies-literature

The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology.

Project description:Amyloid plaques, composed of the amyloid beta-protein (Abeta), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. Abeta fulfills a central role in AD pathogenesis, and reduction of Abeta levels should prove beneficial for AD treatment. Abeta generation is initiated by proteolysis of amyloid precursor protein (APP) by the beta-secretase enzyme BACE1. Bace1 knockout (Bace1(-/-)) mice have validated BACE1 as the authentic beta-secretase in vivo. BACE1 is essential for Abeta generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1(-/-) mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking.

| S-EPMC2662048 | biostudies-literature

Cerebrospinal fluid BACE1 activity and markers of amyloid precursor protein metabolism and axonal degeneration in Alzheimer's disease.

Project description:The objective of this study was to assess cerebrospinal fluid (CSF) ?-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate the enzyme activity with protein markers of APP metabolism and axonal degeneration.BACE1 activity and protein concentrations were measured and analyzed in 342 participants of the Alzheimer's Disease Neuroimaging Initiative, including 99 normal control, 75 stable mild cognitive impairment (MCI), 87 progressive MCI, and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons.No significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APP? (sAPP?) concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APP? and total tau in all four groups and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid ? (A?)1-42 or for plasma A?1-42 and A?1-40.The consistent correlation between BACE1 activity and sAPP? supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.

| S-EPMC4038661 | biostudies-literature

Association studies of 22 candidate SNPs with late-onset Alzheimer's disease.

Project description:Alzheimer's disease (AD) is a complex and multifactorial disease with the possible involvement of several genes. With the exception of the APOE gene as a susceptibility marker, no other genes have been shown consistently to be associated with late-onset AD (LOAD). A recent genome-wide association study of 17,343 gene-based putative functional single nucleotide polymorphisms (SNPs) found 19 significant variants, including 3 linked to APOE, showing association with LOAD (Hum Mol Genet 2007; 16:865-873). We have set out to replicate the 16 new significant associations in a large case-control cohort of American Whites. Additionally, we examined six variants present in positional and/or biological candidate genes for AD. We genotyped the 22 SNPs in up to 1,009 Caucasian Americans with LOAD and up to 1,010 age-matched healthy Caucasian Americans, using 5' nuclease assays. We did not observe a statistically significant association between the SNPs and the risk of AD, either individually or stratified by APOE. Our data suggest that the association of the studied variants with LOAD risk, if it exists, is not statistically significant in our sample.

| S-EPMC2751631 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data