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Biomedical subjects

Y M Kuo

Publications and source records attributed to Y M Kuo.

At least 37 records · Page 2Linked to original sources
PubMed2000

The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease.

Effective therapeutic intervention in Alzheimer disease (AD) will be most effective if it is directed at early events in the pathogenic sequence. The cholinergic deficit may be such an early event. In the present study, the brains of 26 subjects who had no history of cognitive loss and who were in early histopathologic stages of AD (average Braak stage less than II) were examined at autopsy to determine whether a cortical cholinergic decrement was associated with Abeta concentration or deposition. In the superior frontal and inferior temporal gyri, the choline acetyltransferase (ChAT) activity of plaque-containing cases was significantly decreased (p < 0.05, unpaired, two-tailed t-tests), measuring 70.9% and 79.5%, respectively, relative to plaque-free cases. In the inferior temporal gyrus, Spearman's rank correlation analysis showed that ChAT activity had a significant inverse correlation with Abeta concentration (p = 0.075; r = -0.3552). The results indicate that the cholinergic deficit is established at an early histopathologic stage of AD, before the onset of clinical symptoms.

Aged↗
PubMed2000

Cerebral amyloid angiopathy: accumulation of A beta in interstitial fluid drainage pathways in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of beta-amyloid (A beta) peptides in the walls of arteries both in the cortex and meninges. Here, we test the hypothesis that CAA results from the progressive accumulation of A beta in the perivascular interstitial fluid drainage pathways of the brain. Experimental studies have shown that interstitial fluid (ISF) from the rat brain flows along periarterial spaces to join the cerebrospinal fluid (CSF) to drain to cervical lymph nodes. Such lymphatic drainage plays a key role in B-cell and T-cell mediated immunity of the brain. Anatomical studies have defined periarterial ISF drainage pathways in the human brain that are homologous with the lymphatic pathways in the rat brain but are largely separate from the CSF. Periarterial channels in the brain in man are in continuity with those of leptomeningeal arteries and can be traced from the brain to the extracranial portions of the internal carotid arteries related to deep cervical lymph nodes. The pattern of deposition of A beta in senile plaques and in CAA suggests that A beta accumulates in pericapillary and periarterial ISF drainage pathways. A beta could accumulate in CAA due to either (i) increased production of A beta, (ii) reduced solubility of A beta peptides, or (iii) impedance of drainage of A beta along periarterial ISF drainage pathways within the brain and leptomeninges due to aging factors in cerebral arteries. Elucidation of factors that reduce elimination of A beta via perivascular drainage pathways may lead to their rectification and to new strategies for treatment of Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Traumatic brain injury elevates the Alzheimer's amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury.

The increased risk for Alzheimer's Disease (AD) associated with traumatic brain injury (TBI) suggests that environmental insults may influence the development of this age-related dementia. Recently, we have shown that the levels of the beta-amyloid peptide (A beta 1-42) increase in the cerebrospinal fluid (CSF) of patients after severe brain injury and remain elevated for some time after the initial event. The relationships of elevated A beta with markers of blood-brain barrier (BBB) disruption, inflammation, and nerve cell or axonal injury were evaluated in CSF samples taken daily from TBI patients. This analysis reveals that the rise in A beta 1-42 is best correlated with possible markers of neuronal or axonal injury, the cytoskeletal protein tau, neuron-specific enolase (NSE), and apolipoprotein E (ApoE). Similar or better correlations were observed between A beta 1-40 and the three aforementioned markers. These results imply that the degree of brain injury may play a decisive role in determining the levels of A beta 1-42 and A beta 1-40 in the CSF of TBI patients. Inflammation and alterations in BBB may play lesser, but nonetheless significant, roles in determining the A beta level in CSF after brain injury.

Acute-Phase Proteins↗
PubMed2000

Alterations of Alzheimer's disease in the cholesterol-fed rabbit, including vascular inflammation. Preliminary observations.

We determined the levels of endothelial inflammation using MECA-32 antibody and alpha 4 nicotinic receptor subunit densities employing [3H]epibatidine binding in the brains of Alzheimer's disease (AD) patients, cholesterol-fed rabbits, and appropriate controls. We also assessed rabbit brain for beta-amyloid levels and immunohistochemical localization, and for evidence of blood-brain barrier breach using normally-excluded Evans Blue dye. Dietary cholesterol induced a twofold increase in beta-amyloid concentration in rabbit hippocampal cortex, which may be related to the appearance of beta-amyloid immunoreactivity in the neuropil. Epibatidine binding was significantly decreased in AD superior frontal cortex, but unchanged in the superior frontal cortex of cholesterol-fed rabbits. Increased vascular MECA-32 immunoreactivity occurred in AD and cholesterol-fed rabbit brain. Evans Blue dye could be found in the parenchyma of cholesterol-fed rabbits only, and appeared as pockets of dye surrounding small blood vessels. The data suggest that vascular inflammation can lead to breach of the blood-brain barrier, which may produce biochemical derangements in surrounding brain tissue that are conducive to production of beta-amyloid.

Aged↗
PubMed2000

Cortical cholinergic denervation elicits vascular A beta deposition.

Selective destruction of the cholinergic nucleus basalis magnocellularis (nbm) in the rabbit by the p75 neurotrophin receptor (NTR) immunoglobulin G (IgG) complexed to the toxin saporin leads to the deposition of amyloid-beta (A beta) in and around cerebral blood vessels. In some instances, the perivascular A beta resemble the diffuse deposits observed in Alzheimer's disease (AD). We propose that cortical cholinergic deprivation results, among other perturbations, in the loss of vasodilation mediated by acetylcholine. In addition to a dysfunctional cerebral blood flow, alterations in vascular chemistry affecting endothelial and smooth muscle cells may result in cerebral hypoperfusion and a breached blood-brain barrier (BBB). The selective removal of the rabbit nbm and A beta accumulation may serve as an important nontransgenic, and more physiological, model for the testing of pharmacological and immunological agents designed to control the deposition and the deleterious effects of A beta in AD.

Acetylcholine↗
PubMed2000

Elevated A beta and apolipoprotein E in A betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer's disease.

BACKGROUND: Amyloid-beta (A beta) accumulates in plaques and as cerebral amyloid angiopathy (CAA) in the brains of both Alzheimer's disease (AD) patients and transgenic A betaPPswe/tg2576 (tg2576) mice. Increasingly, evidence in humans and mice shows this process to be modulated by apolipoprotein E (apoE). MATERIALS AND METHODS: To explore this relationship, we measured apoE and A beta levels in brains of tg2576 mice and controls at intervals between 2 and 20 months. In addition, A beta concentrations in plasma and muscle of these animals were also quantified. RESULTS: Quite strikingly, we found that the amount of tg2576 mice brain apoE was elevated by an average of 45%, relative to the control mice from 2 months on. The level of brain apoE soared after 14 months to almost 60% greater than the level found in control mice. A beta concentrations in brains before 9 months were less than 2 ng/mg of protein, but by 14 months concentrations rose to 8.7 ng/mg, and by 20 months to 47 ng/mg. In plasma, we noted that the levels of A beta in tg2576 mice declined from above 30 ng/ml prior to 12 months to 14 ng/ml by 14 months. Histology showed that A beta plaques and CAA began to be discernible in the tg2576 mice at about 9 and 20 months of age, respectively. CONCLUSIONS: ApoE was immunocytochemically detected in neuritic plaques that were positive for thioflavine-S. We suggest that the elevation of brain apoE in tg2576 mice participates in an age-related dysregulation of A beta clearance and signals the start of A beta sequestration during the time of cognitive dysfunction.

Aging↗
PubMed1999

High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease.

A previously unrecognized large pool of Abeta was discovered in freshly drawn plasma of patients diagnosed with Alzheimer's disease (AD) and non-demented control subjects. This Abeta pool was revealed after acid denaturation and chromatographic separation of plasma proteins followed by Abeta quantitation in the 4.5 kDa fractions by europium immunoassay. The mean values of Abeta42 in the AD and control individuals amounted to 236 ng/ml and 38 ng/ml, respectively. These Abeta values are on the average far higher than previously measured. Surprisingly, the circulating Abeta42 is about 16 times more abundant than Abeta40 in the AD population. Addition of Abeta to freshly drawn plasma demonstrated the rapid disappearance of Abeta epitopes, as detected by immunochemical techniques, suggesting either proteolytic degradation or Abeta sequestration. Incubation of Abeta with purified plasma proteins and lipoproteins rapidly decreases detectable levels of free Abeta suggesting epitope masking as the likely mechanism. The free and protein-bound Abetab in the circulation may represent a potential source for deposition in the cerebrovasculature and brain parenchyma of AD.

Adult↗
PubMed1999

Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.

We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

Aged↗
PubMed1999

The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency.

Pallid (pa) is 1 of 13 platelet storage pool deficiency (SPD) mouse mutants. pa animals suffer from prolonged bleeding time, pigment dilution, kidney lysosomal enzyme elevation, serum alpha1-antitrypsin activity deficiency and abnormal otolith formation. As with other mouse mutants of this class, characterization of pa mice suggests a defect in organelle biosynthesis. Here we describe the physical mapping, positional cloning, and mutational and functional analysis of the gene that is defective in pa mice. It encodes a ubiquitously expressed, highly charged 172-amino-acid protein (termed pallidin) with no homology to known proteins. We detected a nonsense mutation at codon 69 of this gene in the pallid mutant. In a yeast two-hybrid screen, we discovered that pallidin interacts with syntaxin 13, a t-SNARE protein that mediates vesicle-docking and fusion. We confirmed this interaction by co-immunoprecipitation assay. Immunofluorescence studies corroborate that the cellular distribution of pallidin overlaps that of syntaxin 13. Whereas the mocha and pearl SPD mutants have defects in Ap-3, our findings suggest that pa SPD mutants are defective in a more downstream event of vesicle-trafficking: namely, vesicle-docking and fusion.

Amino Acid Sequence↗
PubMed1999

Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse.

Iron is essential for many cellular functions; consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. Despite the clinical prevalence of these disorders, the mechanism by which dietary iron is absorbed into the body is poorly understood. We have identified a key component in intestinal iron transport by study of the sex-linked anaemia (sla) mouse, which has a block in intestinal iron transport. Mice carrying the sla mutation develop moderate to severe microcytic hypochromic anaemia. Although these mice take up iron from the intestinal lumen into mature epithelial cells normally, the subsequent exit of iron into the circulation is diminished. As a result, iron accumulates in enterocytes and is lost during turnover of the intestinal epithelium. Biochemical studies have failed to identify the underlying difference between sla and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.

Amino Acid Sequence↗
PubMed1998

Elevated low-density lipoprotein in Alzheimer's disease correlates with brain abeta 1-42 levels.

Sera obtained in the immediate postmortem from 100 individuals, 64 neuropathologically diagnosed Alzheimer's disease (AD) cases and 36 nondemented controls, were analyzed for cholesterol, lipoproteins, apolipoproteins (Apo), and triglycerides. All individuals were ApoE genotyped, and the amounts of Abeta (N-40 and N-42) in cerebral cortex of AD and control subjects were determined. When compared to controls, AD individuals had significantly higher LDL cholesterol (P = 0.006), ApoB (P = 0.018), Abeta N-40 (P = 0.024) and Abeta N-42 (P < 0.001), and significantly lower HDL cholesterol (P = 0.040). There were positive correlations between the levels of serum total cholesterol (r = 0.359, P = 0.004), LDL cholesterol (r = 0.328, P = 0.008), and ApoB (r = 0.395, P = 0.001) to the amount of Abeta N-42 in AD brains, but not to Abeta N-40. These correlations were independent of ApoE genotype and were not seen in the control group. The present results suggest for the first time that elevated serum cholesterol, especially in the form of LDL, influences the expression of AD-related pathology.

Aged↗
PubMed1998

Irreversible dimerization/tetramerization and post-translational modifications inhibit proteolytic degradation of A beta peptides of Alzheimer's disease.

Experimental evidence increasingly implicates the beta-amyloid peptide in the pathogenesis of Alzheimer's disease. Beta-amyloid filaments dramatically accumulate in the neuritic plaques and vascular deposits as the result of the brain's inability to clear these structures. In this paper, we demonstrate that in addition to the intrinsic stability of A beta N-42, the time dependent generation of irreversibly associated A beta dimers and tetramers incorporated into A beta filaments are themselves resistant to proteolytic degradation. The presence of post-translational modifications such as isomerization of aspartyls 1 and 7, cyclization of glutamyl 3 to pyroglutamyl and oxidation of methionyl 35, further contribute to the insolubility and stability of A beta. All these factors promote the accumulation of neurotoxic amyloid in the brains of patients with Alzheimer's disease, and should be considered in therapeutic strategies directed towards the dissociation of the brain's A beta filaments.

Alzheimer Disease↗
PubMed1998

Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease.

Cerebral amyloid angiopathy in Alzheimer's disease is characterized by deposition of amyloid beta (Abeta) in cortical and leptomeningeal vessel walls. Although it has been suggested that Abeta is derived from vascular smooth muscle, deposition of Abeta is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Abeta is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer's disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer's disease revealed a pool of soluble Abeta in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer's disease showed that Abeta accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Abeta occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Abeta is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer's disease.

Aged↗
PubMed1998

Traumatic brain injury increases beta-amyloid peptide 1-42 in cerebrospinal fluid.

The beta-amyloid peptides, A beta1-42 and A beta1-40, were quantified in ventricular CSF taken daily for up to 3 weeks from six individuals with severe traumatic brain injury (TBI). There was considerable interindividual variability in the levels of A beta peptides, but in general A beta1-42 levels equalled or exceeded those of A beta1-40. Averaging the daily totals of our trauma cohort revealed that the levels of A beta1-42 and A beta1-40 rose after injury, peaking in the first week and then declining toward control levels over the next 2 weeks. A beta1-42 levels were on average two to three times higher in the trauma cohort than in CSF from nontrauma samples. Compared with nontrauma samples, the A beta1-40/A beta1-42 ratio decreased about fivefold in the trauma patients, further indicative of increased A beta1-42 levels. The ratio remained low at all time points studied. No change was measured in the levels of beta-amyloid precursor protein during the same interval. These results suggest that A beta1-42 becomes elevated in the CSF after severe brain trauma.

Adult↗
PubMed1998

GB virus C/hepatitis G virus infection in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: GB virus C or hepatitis G virus (GBV-C/HGV) can be transmitted parenterally, very likely sharing common routes of transmission with hepatitis C virus (HCV). Patients on maintenance haemodialysis have been shown to be at increased risk of the novel GBV-C/HGV infection. Whether continuous ambulatory peritoneal dialysis (CAPD) can reduce the risk of GBV-C/HGV infection as demonstrated for HCV remains unknown. METHODS: Serum GBV-C/HGV RNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) with nested primers derived from the 5'-untranslated region (5' UTR) of the viral genome. We investigated the prevalence of GBV-C/HGV viraemia in 60 patients on CAPD and the possible routes of transmission. One hundred healthy adults were selected as controls. RESULTS: The prevalence of GBV-C/HGV viraemia in CAPD patients was 23.3%, compared with 1% of healthy adults (P<0.05). Compared with patients without hepatitis B virus (HBV), HCV or GBV-C/HGV infection (n=39), those with GBV-C/HGV infection alone (n=11) have received more blood transfusions (mean 18.9 units vs 6.8 units, P<0.05). There were no significant differences between the viraemic and nonviraemic groups with respect to age, gender, duration of CAPD, duration of previous haemodialysis, previous history of surgery and co-infection with HBV or HCV. Three of the 11 (27.3%) patients with GBV-C/HGV infection alone had elevated serum alanine aminotransferase (ALT) level, and the frequency was significantly higher than that of patients negative for the viraemia (0%, P<0.05). In addition, the mean serum ALT level was also higher in the group with GBV-C/HGV infection compared with those without HBV, HCV and GBV-C/HGV infections (22.3+/-16.9 U/l vs 14.0+/-6.8 U/l, P<0.01). CONCLUSIONS: Patients on CAPD are at increased risk of GBV-C/HGV infection, and the risk parallels the number of previously transfused units of blood.

Adolescent↗