Dataset Information

Amyloid-beta dynamics correlate with neurological status in the injured human brain.

ABSTRACT: The amyloid-beta peptide (Abeta) plays a central pathophysiological role in Alzheimer's disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Abeta concentrations and neurological status, with Abeta concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Abeta concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Abeta concentration.

SUBMITTER: Brody DL

PROVIDER: S-EPMC2577829 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Amyloid-beta dynamics correlate with neurological status in the injured human brain.

Brody David L DL Magnoni Sandra S Schwetye Kate E KE Spinner Michael L ML Esparza Thomas J TJ Stocchetti Nino N Zipfel Gregory J GJ Holtzman David M DM

Science (New York, N.Y.) 20080801 5893

The amyloid-beta peptide (Abeta) plays a central pathophysiological role in Alzheimer's disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Abeta concentrations ...[more]

PMID: 18755980

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Project description:Amyloid precursor protein (APP) is the precursor to Aβ plaques. The cytoplasmic domain of APP mediates attachment of vesicles to molecular motors for axonal transport. In APP-KO mice, transport of Mn2+ is decreased. In old transgenic mice expressing mutated human (APPSwInd) linked to Familial Alzheimer's Disease, with both expression of APPSwInd and plaques, the rate and destination of Mn2+ axonal transport is altered, as detected by time-lapse manganese-enhanced magnetic resonance imaging (MEMRI) of the brain in living mice. To determine the relative contribution of expression of APPSwInd versus plaque on transport dynamics, we developed a Tet-off system to decouple expression of APPSwInd from plaque, and then studied hippocampal to forebrain transport by MEMRI. Three groups of mice were compared to wild-type (WT): Mice with plaque and APPSwInd expression; mice with plaque but suppression of APPSwInd expression; and mice with APPSwInd suppressed from mating until 2 weeks before imaging with no plaque. MR images were captured before at successive time points after stereotactic injection of Mn2+ (3-5 nL) into CA3 of the hippocampus. Mice were returned to their home cage between imaging sessions so that transport would occur in the awake freely moving animal. Images of multiple mice from the three groups (suppressed or expressed) together with C57/B6J WT were aligned and processed with our automated computational pipeline, and voxel-wise statistical parametric mapping (SPM) performed. At the conclusion of MR imaging, brains were harvested for biochemistry or histopathology. Paired T-tests within-group between time points (p = 0.01 FDR corrected) support the impression that both plaque alone and APPSwInd expression alone alter transport rates and destination of Mn2+ accumulation. Expression of APPSwInd in the absence of plaque or detectable Aβ also resulted in transport defects as well as pathology of hippocampus and medial septum, suggesting two sources of pathology occur in familial Alzheimer's disease, from toxic mutant protein as well as plaque. Alternatively mice with plaque without APPSwInd expression resemble the human condition of sporadic Alzheimer's, and had better transport. Thus, these mice with APPSwInd expression suppressed after plaque formation will be most useful in preclinical trials.

Dataset Information

Amyloid-beta dynamics correlate with neurological status in the injured human brain.

Publications

Amyloid-beta dynamics correlate with neurological status in the injured human brain.

Similar Datasets

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