A novel protein, amyloid precursor-like protein 2, is present in human brain, cerebrospinal fluid and conditioned media.
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ABSTRACT:
SUBMITTER: Webster MT
PROVIDER: S-EPMC1135859 | biostudies-other | 1995 Aug
REPOSITORIES: biostudies-other
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Project description:BackgroundSoluble fragments of the amyloid precursor protein (APP) generated by ?- and ?-secretases, sAPP? and sAPP?, have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for the clinical diagnosis of Alzheimer's disease (AD). However, the capacity of these soluble proteins to assemble has not been explored and could be relevant. Our aim is to characterize possible sAPP oligomers that could contribute to the quantification of sAPP? and sAPP? in CSF by ELISA, as well as to characterize the possible presence of soluble full-length APP (sAPPf).ResultsWe employed co-immunoprecipitation, native polyacrylamide gel electrophoresis and ultracentrifugation in sucrose density gradients to characterize sAPP oligomers in CSF. We have characterized the presence of sAPPf in CSF from NDC and AD subjects and demonstrated that all forms, including sAPP? and sAPP?, are capable of assembling into heteromers, which differ from brain APP membrane-dimers. We measured sAPPf, sAPP? and sAPP? by ELISA in CSF samples from AD (n?=?13) and non-disease subjects (NDC, n?=?13) before and after immunoprecipitation with antibodies against the C-terminal APP or against sAPP?. We demonstrated that these sAPP heteromers participate in the quantification of sAPP? and sAPP? by ELISA. Immunoprecipitation with a C-terminal antibody to remove sAPPf reduced by ~30% the determinations of sAPP? and sAPP? by ELISA, whereas immunoprecipitation with an APP? antibody reduced by ~80% the determination of sAPPf and sAPP?.ConclusionsThe presence of sAPPf and sAPP heteromers should be taken into consideration when exploring the levels of sAPP? and sAPP? as potential CSF biomarkers.
| S-EPMC4298044 | biostudies-literature
Project description:In a previous study, we reported that levels of two types of protein species-a type of ~55-kDa species and a type of ~15-kDa species-are elevated in the lumbar cerebrospinal fluid (CSF) of cognitively intact elderly individuals who are at risk for Alzheimer's disease (AD). These species are immunoreactive to the monoclonal antibody 6E10, which is directed against amino acids 6-10 of amyloid-β (Aβ), and their levels correlate with levels of total tau and tau phosphorylated at Thr181. In this study, we investigated the molecular composition of these AD-related proteins using immunoprecipitation (IP)/Western blotting coupled with IP/mass spectrometry. We show that canonical Aβ1-40/42 peptides, together with amyloid-β precursor protein (APP) fragments located N-terminally of Aβ, are present in the ~55-kDa, 6E10-immunoreactive species. We demonstrate that APP fragments located N-terminally of Aβ, plus the N-terminal region of Aβ, are present in the ~15-kDa, 6E10-immunoreactive species. These findings add to the catalog of AD-related Aβ/APP species found in CSF and should motivate further study to determine whether these species may serve as biomarkers of disease progression.
| S-EPMC6394962 | biostudies-literature
Project description:The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APP?, APP? or A?42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APP?, APP?, and A?42, AD risk and age-at-onset while taking into account age, gender, race and APOE ?4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APP? levels. In controls, the rs514049 CC genotype had higher APP? levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APP? levels in an AD specific manner.
| S-EPMC3065534 | biostudies-literature
Project description:Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer's disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid ?, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid ?1-42, amyloid ?38/?40/?42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid ?42/amyloid ?38 and the amyloid ?42/amyloid ?40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid ?1-42, or amyloid ?38/?40/?42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients.
| S-EPMC3572463 | biostudies-literature
Project description:In this study we have profiled the free sterol content of cerebrospinal fluid by a combination of charge tagging and liquid chromatography-tandem mass spectrometry. Surprisingly, the most abundant cholesterol metabolites were found to be C(27) and C(24) intermediates of the bile acid biosynthetic pathways with structures corresponding to 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid (7.170 +/- 2.826 ng/ml, mean +/- S.D., six subjects), 3beta-hydroxycholest-5-en-26-oic acid (0.416 +/- 0.193 ng/ml), 7alpha,x-dihydroxy-3-oxocholest-4-en-26-oic acid (1.330 +/- 0.543 ng/ml), and 7alpha-hydroxy-3-oxochol-4-en-24-oic acid (0.172 +/- 0.085 ng/ml), and the C(26) sterol 7alpha-hydroxy-26-norcholest-4-ene-3,x-dione (0.204 +/- 0.083 ng/ml), where x is an oxygen atom either on the CD rings or more likely on the C-17 side chain. The ability of intermediates of the bile acid biosynthetic pathways to activate the liver X receptors (LXRs) and the farnesoid X receptor was also evaluated. The acidic cholesterol metabolites 3beta-hydroxycholest-5-en-26-oic acid and 3beta,7alpha-dihydroxycholest-5-en-26-oic acid were found to activate LXR in a luciferase assay, but the major metabolite identified in this study, i.e. 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid, was not an LXR ligand. 7Alpha-hydroxy-3-oxocholest-4-en-26-oic acid is formed from 3beta,7alpha-dihydroxycholest-5-en-26-oic acid in a reaction catalyzed by 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase (HSD3B7), which may thus represent a deactivation pathway of LXR ligands in brain. Significantly, LXR activation has been found to reduce the symptoms of Alzheimer disease (Fan, J., Donkin, J., and Wellington C. (2009) Biofactors 35, 239-248); thus, cholesterol metabolites may play an important role in the etiology of Alzheimer disease.
| S-EPMC2836072 | biostudies-literature
Project description:IntroductionSubcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers.MethodsWe included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-β (Aβ)x-38, Aβx-40, Aβx-42, as well as soluble amyloid precursor protein (sAPP)-α and sAPP-β.ResultssAPP-β was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-β moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses.DiscussionSSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-β could be additional tools to diagnose SSVD.HighlightsPatients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-β and disturbances of the blood-brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.
| S-EPMC8949877 | biostudies-literature
Project description:The proteolytic processing of human amyloid precursor protein (APP) into shorter aggregating amyloid β (Aβ)-peptides, e.g., Aβ1-42, is considered a critical step in the pathogenesis of Alzheimer's disease (AD). Although APP is a well-known membrane glycoprotein carrying both N- and O-glycans, nothing is known about the occurrence of released APP/Aβ glycopeptides in cerebrospinal fluid (CSF). We used the 6E10 antibody and immunopurified Aβ peptides and glycopeptides from CSF samples and then liquid chromatography-tandem mass spectrometry for structural analysis using collision-induced dissociation and electron capture dissociation. In addition to 33 unglycosylated APP/Aβ peptides, we identified 37 APP/Aβ glycopeptides with sialylated core 1 like O-glycans attached to Thr(-39, -21, -20, and -13), in a series of APP/AβX-15 glycopeptides, where X was -63, -57, -52, and -45, in relation to Asp1 of the Aβ sequence. Unexpectedly, we also identified a series of 27 glycopeptides, the Aβ1-X series, where X was 20 (DAEFRHDSGYEVHHQKLVFF), 19, 18, 17, 16, and 15, which were all uniquely glycosylated on Tyr10. The Tyr10 linked O-glycans were (Neu5Ac)(1-2)Hex(Neu5Ac)HexNAc-O- structures with the disialylated terminals occasionally O-acetylated or lactonized, indicating a terminal Neu5Acα2,8Neu5Ac linkage. We could not detect any glycosylation of the Aβ1-38/40/42 isoforms. We observed an increase of up to 2.5 times of Tyr10 glycosylated Aβ peptides in CSF in six AD patients compared to seven non-AD patients. APP/Aβ sialylated O-glycans, including that of a Tyr residue, the first in a mammalian protein, may modulate APP processing, inhibiting the amyloidogenic pathway associated with AD.
| S-EPMC3141957 | biostudies-literature
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
Project description:This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer's disease (AD). Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by ?-secretase. The level of the 25-kDa APP-CTF was evaluated in three independent CSF sample sets of patients and controls. The CSF level of this 25-kDa CTF is higher in subjects with autosomal dominant AD linked to PSEN1 mutations, in demented Down syndrome individuals and in sporadic AD subjects compared to age-matched controls. Our data suggest that APP-CTF could be a potential diagnostic biomarker for AD.
| S-EPMC5449401 | biostudies-literature
Project description:BackgroundNeurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment.ObjectiveThe objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH.MethodsCSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses.ResultsCSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95).ConclusionsHerein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant.
| S-EPMC4349693 | biostudies-literature