CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.
The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.
Background
The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer’s disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories.
Methods
Data from the first nine rounds of the Alzheimer’s Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection.
Results
A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP).
Conclusions
The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
The 14-3-3 protein is a family of acidic proteins present exclusively in the brain and is believed to have a function in monoamine biosynthesis because of its ability to activate tyrosine hydroxylase and tryptophan hydroxylase in the presence of Ca2+/calmodulin-dependent protein kinase type II. In this study, we resolved bovine brain 14-3-3 protein into seven polypeptide components by means of reversed-phase chromatography and determined the amino acid sequence of one of these components (v chain) by cloning its cDNA from a bovine cerebellum cDNA library. The is-chain mRNA is 1.8 kilobases long and encodes a polypeptide of 246 amino acids and Mr 28,221. Computer-assisted analysis of the sequence indicates that the g chain exhibits no internal sequence repeats, nor does it have significant sequence similarity to other proteins with known amino acid sequence. However, the q chain appears to consist of two structural regions that are distinguishable in their clearly different charge characteristics: the almost neutral amino-terminal region and the strongly acidic carboxyl-terminal region. The structural features of the tg chain and the domain organization of tyrosine and tryptophan hydroxylases suggest that the 14-3-3 protein binds to the regulatory domain ofthe phosphorylated hydroxylases through its acidic carboxyl-terminal region and activates the hydroxylases by inducing an active conformation.Nerve stimulation, neurotransmitters, and certain growth hormones have been shown to accelerate biosynthesis of catecholamines and of neurotransmitter serotonin in the target cells (1). This acceleration is thought to result from an increase in the activity of tyrosine hydroxylase (TyrOHase; tyrosine 3-monooxygenase, EC 1.14.16.2) or tryptophan hydroxylase (TrpOHase; tryptophan 5-monooxygenase, EC 1.14.16.4), the initial and rate-limiting enzymes in the pathway of monoamine biosynthesis. Various mechanisms appear to be involved in this regulatory process: the induction of enzyme molecules, the increased biosynthesis of the coenzyme tetrahydrobiopterin, and the phosphorylation of enzymes through the action of protein kinases (1). The phosphorylation is coupled with a series of cellular second
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