Amyloid Precursor Protein In Cerebrospinal Fluid Research Articles

Cerebrospinal fluid amyloid precursor protein as a potential biomarker of fatigue in multiple sclerosis: A pilot study

BackgroundFatigue is the major cause of disability in MS. Fatigue has been suggested to be primary, part of the neurological disease; it can also be secondary to other diseases outside the CNS or exist as a separate comorbidity. The only forms of measurement currently available are through subjective standardized questionnaires, which are not able to identify primary MS-related fatigue. Therefore, there is a need for objective biomarkers of fatigue in MS. This study explored the viability of 17 possible biomarkers of primary fatigue in MS. Our chosen biomarker panel represents the function and health of different parts of the CNS. MethodsWe evaluated 31 MS patients and 17 healthy controls using the Fatigue Severity Scale (FSS) and Insomnia Severity Index (ISI). We assessed clinical parameters and collected CSF from all participants to analyze 17 biomarkers, some of which in multiple targeted sequences, reflecting structural and functional changes in the brain. Based on FSS scores, MS was divided into MS-Fatigue (MS-F, FSS ≥ 4) and MS-NoFatigue (MS-NoF, FSS < 4). ResultsMS-F had significantly lower levels of amyloid precursor protein (APP) peptides than MS-NoF (p = 0.005, p = 0.011). The only biomarker correlating with FSS in any group was APP in MS (r = -0.47, -0.52; p = 0.007, 0.002). APP did not correlate with any clinical parameter in MS but correlated with multiple markers. In MS, FSS correlated with the ISI and months since diagnosis. ConclusionAlthough the mechanisms remain unknown, altered APP metabolism in MS seems to be associated with fatigue. APP should be evaluated as a biomarker of the role of structural MS pathology in the development of fatigue in individual MS patients.

Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity.

Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae.

Cerebrospinal fluid neuroplasticity-associated protein levels in patients with psychiatric disorders: a multiplex immunoassay study

To examine the role of neuroplasticity in the pathology of psychiatric disorders, we measured cerebrospinal fluid (CSF) neuroplasticity-associated protein levels. Participants were 94 patients with schizophrenia, 68 with bipolar disorder (BD), 104 with major depressive disorder (MDD), and 118 healthy controls, matched for age, sex, and ethnicity (Japanese). A multiplex immunoassay (22-plex assay) was performed to measure CSF neuroplasticity-associated protein levels. Among 22 proteins, 11 were successfully measured in the assay. CSF amyloid precursor protein (APP) and glial cell-derived neurotrophic factor (GDNF) levels were significantly lower in patients with schizophrenia, and CSF APP and neural cell adhesion molecule (NCAM)-1 levels were significantly lower in patients with BD, than in healthy controls (all p < 0.05). Positive and Negative Syndrome Scale total, positive, and general scores were significantly and positively correlated with CSF hepatocyte growth factor (HGF) (p < 0.01) and S100 calcium-binding protein B (S100B) (p < 0.05) levels in patients with schizophrenia. Young mania-rating scale score was significantly and positively correlated with CSF S100B level in patients with BD (p < 0.05). Hamilton Depression Rating Scale, core, sleep, activity, somatic anxiety, and delusion subscale scores were significantly and positively correlated with CSF HGF level, while sleep subscale score was positively correlated with CSF S100B and VEGF receptor 2 levels in patients with MDD (p < 0.05). Our results suggest that CSF APP, GDNF, and NCAM-1 levels are associated with psychiatric disorders, and that CSF HGF, S100B, and VEGF receptor 2 levels are related to psychiatric symptoms.

Lumbar Cerebrospinal Fluid Biomarkers of Posthemorrhagic Hydrocephalus of Prematurity: Amyloid Precursor Protein, Soluble Amyloid Precursor Protein α, and L1 Cell Adhesion Molecule.

Intraventricular hemorrhage (IVH) is the most frequent, severe neurological complication of prematurity and is associated with posthemorrhagic hydrocephalus (PHH) in up to half of cases. PHH requires lifelong neurosurgical care and is associated with significant cognitive and psychomotor disability. Cerebrospinal fluid (CSF) biomarkers may provide both diagnostic information for PHH and novel insights into its pathophysiology. To explore the diagnostic ability of candidate CSF biomarkers for PHH. Concentrations of amyloid precursor protein (APP), soluble APPα (sAPPα), soluble APPβ, neural cell adhesion molecule-1 (NCAM-1), L1 cell adhesion molecule (L1CAM), tau, phosphorylated tau, and total protein (TP) were measured in lumbar CSF from neonates in 6 groups: (1) no known neurological disease (n = 33); (2) IVH grades I to II (n = 13); (3) IVH grades III to IV (n = 12); (4) PHH (n = 12); (5) ventricular enlargement without hydrocephalus (n = 10); and (6) hypoxic ischemic encephalopathy (n = 13). CSF protein levels were compared using analysis of variance, and logistic regression was performed to examine the predictive ability of each marker for PHH. Lumbar CSF levels of APP, sAPPα, L1CAM, and TP were selectively increased in PHH compared with all other conditions (all P < .001). The sensitivity, specificity, and odds ratios of candidate CSF biomarkers for PHH were determined for APP, sAPPα, and L1CAM; cut points of 699, 514, and 113ng/mL yielded odds ratios for PHH of 80.0, 200.0, and 68.75, respectively. Lumbar CSF APP, sAPPα, L1CAM, and TP were selectively increased in PHH. These proteins, and sAPPα, in particular, hold promise as biomarkers of PHH and provide novel insight into PHH-associated neural injury and repair.

Transmembrane Amyloid-Related Proteins in CSF as Potential Biomarkers for Alzheimer's Disease.

In the continuing search for new cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), reasonable candidates are the secretase enzymes involved in the processing of the amyloid precursor protein (APP), as well as the large proteolytic cleavage fragments sAPPα and sAPPβ. The enzymatic activities of some of these secretases, such as BACE1 and TACE, have been investigated as potential AD biomarkers, and it has been assumed that these activities present in human CSF result from the soluble truncated forms of the membrane-bound enzymes. However, we and others recently identified soluble forms of BACE1 and APP in CSF containing the intracellular domains, as well as the multi-pass transmembrane presenilin-1 (PS1) and other subunits of γ-secretase. We also review recent findings that suggest that most of these soluble transmembrane proteins could display self-association properties based on hydrophobic and/or ionic interactions leading to the formation of heteromeric complexes. The oligomerization state of these potential new biomarkers needs to be taken into consideration for assessing their real potential as CSF biomarkers for AD by adequate molecular tools.

Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity.

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.

F2‐03‐04: Circadian patterns of beta‐amyloid in human cerebrospinal fluid and plasma

The amyloid hypothesis predicts that increased production or decreased clearance of amyloid-beta (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer's disease (AD). Changes in amyloid proteins, such as decreased cerebrospinal fluid (CSF) Aβ42 have been recognized as a biomarker for AD. However, the dynamics of Aβ concentrations over time are not well understood. Hourly CSF and plasma samples were obtained over a 36-hour study period in three groups of human volunteers: a dementia group with amyloid deposition, an age-matched control group, and a younger control group. We investigated dynamic patterns of Aβ peptides (Aβ40 and Aβ42 in CSF and plasma using bead-based Luminex XMAP assays), and Amyloid Precursor Protein (APP) (APP-α and APP-β in CSF using ELISA assays). We then analyzed the effects of aging and amyloidosis on circadian patterns and correlations between CSF and plasma Aβ peptides. Circadian patterns were observed in CSF and plasma Aβ, with decreased amplitudes with aging. Further, CSF APP also demonstrated a circadian pattern. No significant correlations were found between plasma and CSF Aβ levels on an hourly or individual basis. We also found that CSF APPα, APPβ, Aβ40, and Aβ42 are highly positively correlated in all participants without amyloidosis. However, in participants with amyloidosis, there is no correlation of Aβ42 to the other APP metabolites, suggesting that normal physiologic regulation of CSF Aβ42 is impaired in the presence of amyloidosis. This study suggests amyloid proteins in both central and peripheral compartments are dynamic, and regulated in a circadian pattern that is part of the normal dynamic physiologic control of Aβ concentrations. Regulatory mechanisms of these proteins may be altered with aging and amyloidosis. The lack of correlation of plasma and CSF Aβ levels suggest plasma Aβ concentrations can not be used for surrogates of central Aβ concentrations. These findings support an active circadian regulation of Aβ and may provide insight into the pathophysiological changes in AD.

Effects of cerebrovascular disease on amyloid precursor protein metabolites in cerebrospinal fluid

BackgroundAlzheimer's disease (AD) and cerebrovascular disease (CVD) including chronic small vessel disease of the brain (SVD) are the most frequent causes of dementia. AD is associated with metabolism of amyloid precursor protein (APP) and low levels of amyloid-β peptide (Aβ) X-42 in the cerebrospinal fluid (CSF). CVD and SVD are established risk factors for AD, brain white matter lesions (WML) are established surrogate markers for SVD and are also associated with reduced CSF AβX-42.A cohort survey was performed to examine whether SVD or acute CVD affects APP metabolism and to explore a potential association between WML and APP metabolism in two groups; cognitively impaired patients, subjective and mild (SCI and MCI) and stroke patients. Through measurements of CSF APP metabolite levels in patients with a wide range of WML volumes, this study aimed to determine how SVD influences APP metabolism.MethodsSixty-three patients were included: 37 with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI) without stroke, and 26 after acute stroke. Chronic and acute WML volume and infarct volume were determined by magnetic resonance imaging (MRI) post-scan processing, and CSF levels of α- and β-cleaved soluble APP (sAPP-α and sAPP-β, AβX-38, AβX-40 and AβX-42) were determined. The Mann-Whitney test was used to compare the patient groups. Chronic and acute WML volumes, infarct volume, age, and sex were used as predictors for CSF biomarker levels in linear regression analysis.ResultsCSF levels of sAPP-α and sAPP-β were strongly correlated (r = 0.95, p < 0.001) and lower levels of these biomarkers were found in the stroke group than in the SCI/MCI group; median sAPP-α 499.5 vs. 698.0 ng/mL (p < 0.001), sAPP-β 258.0 vs. 329.0 ng/mL (p < 0.005). CSF levels of sAPP-α, sAPP-β, AβX-38, AβX-40 and AβX-42 were inversely correlated with chronic WML volume (p ≤ 0.005; p ≤ 0.01; p ≤ 0.01; p ≤ 0.05; p ≤ 0.05 respectively), but not with acute WML or infarct volumes.ConclusionsLower CSF levels of sAPP-α and sAPP-β in the stroke group than in the SCI/MCI group and an inverse correlation with chronic WML indicate that ischemia lowers the levels of CSF sAPP metabolites and suggests that APP axonal transport or metabolism may be affected in SVD of the brain.

Identification of novel N-terminal fragments of amyloid precursor protein in cerebrospinal fluid

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. Two pathological hallmarks in the brain of AD patients are neurofibrillary tangles and senile plaques. The plaques consist mainly of β-amyloid (Aβ) peptides that are produced from the amyloid precursor protein (APP), by sequential cleavage by β- and γ-secretase. Most previous studies have been focused on the C-terminal fragments of APP, where the Aβ sequence is localized. The purpose of this study was to search for N-terminal fragments of APP in cerebrospinal fluid (CSF) using mass spectrometry (MS). By using immunoprecipitation (IP) combined with matrix-assisted laser desorption/ionization time-of-flight MS as well as nanoflow liquid chromatography coupled to high resolution tandem MS we were able to detect and identify six novel N-terminal APP fragments [APP (18–119), APP (18–121), APP (18–122), APP (18–123), APP (18–124) and APP (18–126)], having molecular masses of approximately 12 kDa. The presence of these APP derivatives in CSF was also verified by Western blot analysis. Two pilot studies using either IP-MS or Western blot analysis indicated slightly elevated levels of N-terminal APP fragments in CSF from AD patients compared with controls, which are in need of replications in independent and larger patient materials.

Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation.

A number of in vitro studies have shown that activation of muscarinic receptors by cholinergic agonists stimulates the nonamyloidogenic, alpha-secretase-processing pathway of amyloid precursor protein (APP). To determine whether increased cholinergic neurotransmission can modify the APP processing in vivo, we administered a muscarinic receptor agonist (RS86) to normal or aged rats and rats with severe basal forebrain cholinergic deficits (induced by 192 IgG-saporin). The levels of the cell-associated APP in neocortex, hippocampus, and striatum, as well as the secreted form of APP (APPs) in cerebrospinal fluid, were examined by Western blots. Additionally, we investigated the association between the altered APP levels and behavioral deficits caused by cholinergic lesions. We found that treatment with muscarinic receptor agonist resulted in decreased APP levels in neocortex and hippocampus and increased levels of APPs in cerebrospinal fluid. Regulation of APP processing by the muscarinic agonist treatment occurred not only in normal rats, but also in aged and cholinergic denervated rats that model this aspect of Alzheimer's disease. Interestingly, we found that elevation of APP in neocortex correlated with the cognitive deficits in water-maze testing of rats with cholinergic dysfunction. These data indicate that increased cholinergic neurotransmission can enhance nonamyloidogenic APP processing in intact and lesioned rats and that APP may be involved in cognitive performance.

Quantitative changes in the amyloid βA4 precursor protein in Alzheimer cerebrospinal fluid

The major three secretory isoforms of Alzheimer βA4 amyloid precursor protein (APP) were quantified in cerebrospinal fluid (CSF) using (1) a newly developed enzyme-linked immunosorbent assay (ELISA) and (2) densitometric analysis of CSF Western blots. The protease inhibitor-containing APP751/770 isoforms represented an average of 10.5% of total APP in CSF of patients with Alzheimer's disease (AD, n = 22), multi-infarct dementia (MID, n = 5) and normal controls ( n = 10). APP levels in CSF did not depend on total CSF protein. Both findings are inconsistent with a hematogeneous origin of APP in CSF and suggest an intracerebral source. Total APP, APP695 and APP751/770 were significantly decreased in the AD and in the MID groups, but were not correlated to the ages of patients or controls.