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

ABSTRACT: 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.

SUBMITTER: Perneczky R

PROVIDER: S-EPMC4038661 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Perneczky Robert R Alexopoulos Panagiotis P

Alzheimer's & dementia : the journal of the Alzheimer's Association 20131113 5 Suppl

<h4>Objective</h4>The objective of this study was to assess cerebrospinal fluid (CSF) β-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.<h4>Methods</h4>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 ...[more]

PMID: 24239250

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Project description:Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid ?42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid ?42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

Dataset Information

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

Publications

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

Similar Datasets

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