Biomedical subjects

K Duff

Publications and source records attributed to K Duff.

At least 19 recordsLinked to original sources

PubMed2004

Application of a non-linear image registration algorithm to quantitative analysis of T2 relaxation time in transgenic mouse models of AD pathology.

Transgenic mouse models have been essential for understanding the pathogenesis of Alzheimer's disease (AD) including those that model the deposition process of beta-amyloid (Abeta). Several laboratories have focused on research related to the non-invasive detection of early changes in brains of transgenic mouse models of Alzheimer's pathology. Most of this work has been performed using regional image analysis of individual mouse brains and pooling the results for statistical assessment. Here we report the implementation of a non-linear image registration algorithm to register anatomical and transverse relaxation time (T2) maps estimated from MR images of transgenic mice. The algorithm successfully registered mouse brain magnetic resonance imaging (MRI) volumes and T2 maps, allowing reliable estimates of T2 values for different regions of interest from the resultant combined images. This approach significantly reduced the data processing and analysis time, and improved the ability to statistically discriminate between groups. Additionally, 3D visualization of intra-regional distributions of T2 of the resultant registered images provided the ability to detect small changes between groups that otherwise would not be possible to detect.

Algorithms↗

PubMed2003

Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes.

Senile plaques composed mainly of beta-amyloid (Abeta) and neurofibrillary tangles principally composed of hyperphosphorylated tau are the major pathological features of Alzheimer's disease (AD). Despite the fact that increased expression of amyloid precursor protein (APP) and presenilin-1 (PS1) transgenes in mice lead to increased Abeta deposition in plaquelike structures in the brain, little is known about the nature and distribution of tau in these mice. Therefore the relationship between Abeta and hyperphosphorylated tau was investigated in mice carrying mutant APP and mutant PS1 transgenes using both light (LM) and electron microscopy (EM) with immunocytochemistry. LM immunocytochemistry revealed cerebral Abeta deposits to be present from 8 weeks of age, whereas hyperphosphorylated tau was not detected until 24 weeks of age, when it appeared as punctate deposits in close association with the Abeta deposits in the cortex and hippocampus. However, dystrophic neurites were not as heavily immunolabeled as they are in AD brain. EM revealed that aggregations of straight filaments (10-12 nm wide) were present in some cellular processes at the periphery of Abeta plaques in 8-month-old APP/PS1 mice. In one such mouse, single filaments and paired filaments showing a helical configuration (50-55 nm half-period, 25 nm max. width) were present in a dark, atrophic hippocampal neuron. Immunogold labeling of APP/PS1 mouse brain revealed hyperphosphorylated tau epitopes in some dystrophic neurites from 24 weeks of age that were similar to those present in AD. These results suggest that hyperphosphorylated tau appears in APP/PS1 mouse brain after the onset of Abeta deposition and although it is associated with Abeta deposits, its distribution is not identical to that in AD.

Adult↗

PubMed2002

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.

Despite extensive deposition of putatively neurotoxic amyloid-beta (Abeta) protein in the brain, it has not been possible to demonstrate an association of Abeta deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared Abeta deposition, Abeta morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar Abeta deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that Abeta develops neurotoxic properties in vivo when it adopts a fibrillar beta-pleated sheet conformation.

Alzheimer Disease↗

PubMed2002

Modulation of A(beta) peptides by estrogen in mouse models.

Clinical studies have shown that estrogen deprivation through menopause is a risk factor in both the initiation and progression of Alzheimer's disease (AD) and that estrogen replacement therapy may be protective. One of the major pathological features in the human AD brain is the senile plaque, a proteinaceous structure composed mainly of heterogeneous peptides collectively known as A-beta (A(beta)). In vitro studies have linked estrogen with A(beta) modulation, suggesting that one-way that estrogen depletion at menopause may exacerbate the features of AD is through A(beta) accumulation. To test this, two studies were performed on transgenic models of amyloidosis. Firstly, transgenic mice without detectable amyloid aggregates were subjected to ovariectomy and estradiol supplementation, and A(beta) levels were assessed. Secondly, the effects of estrogen modulation were assessed in mice at an age when plaques would be forming initially. Overall, A(beta) levels were higher in estrogen-deprived mice than intact mice, and this effect could be reversed through the administration of estradiol. These data suggest that, in vivo, estrogen depletion leads to the accumulation of A(beta) in the CNS, which can be reversed through replacement of estradiol. These results provide evidence that post-menopausal estrogen depletion may be linked to an increased risk of AD through A(beta) modulation.

Amyloid beta-Peptides↗

PubMed2001

Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes.

The basalo-cortical cholinergic system was characterized in mice expressing mutant human genes for presenilin-1 (PS1), amyloid precursor protein (APP), and combined PS/APP. Dual immunocytochemistry for ChAT and A beta revealed swollen cholinergic processes within cortical plaques in both APP and PS/APP brains by 12 months, suggesting aberrant sprouting or redistribution of cholinergic processes in response to amyloid deposition. At 8 months, cortical and subcortical ChAT activity was normal (PS/APP) or elevated (PS, APP frontal cortex), while cholinergic cell counts (nBM/SI) and receptor binding were unchanged. ChAT mRNA was up-regulated in the nBM/SI of all three transgenic lines at 8 months. The data indicate that the basal forebrain cholinergic system does not degenerate in mice expressing AD-related transgenes, even in mice with extreme amyloid load. The

Acetylcholine↗

PubMed2001

Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes.

Mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) lead to an increase in beta-amyloid (Abeta) production. Despite the fact that a number of transgenic mice develop cerebral Abeta plaques, few have been subjected to ultrastructural investigation and the sequence of events leading to Abeta plaque formation is unclear. We therefore investigated the doubly transgenic (mutant APP(K670N,M671L)-mutant PS1(M146L)) mouse, which develops Abeta deposits much earlier than singly transgenic littermates. Widespread Abeta plaques with or without a distinct core were found in gray matter. Abeta plaques were also present in white matter. Astrocytosis was greater around gray matter plaques than around white matter plaques. In some plaques, Abeta cores were associated with cell profiles containing prominent endoplasmic reticulum and a homogeneous cytoplasm that appeared to be neuronal. The morphology and location of other profiles indicated them to be microglia or oligodendrocytes. Some Abeta fibrils appeared to lie within these profiles, but they may have been simply surrounded by the cell profile since the profile membrane was not always visible. Dark atrophic neurons, whose morphology suggested that they were apoptotic, were present around gray matter plaques. Cerebrovascular Abeta deposition was also observed in the brains of APP/PS1 transgenic mice. Thus, the amyloid deposition and neuropathology observed in APP/PS1 mouse brain are similar to those in Alzheimer's disease and they appear to develop earlier and become more severe than in the other transgenic models currently available.

Aging↗

PubMed2001

Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.

alpha-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human alpha-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human alpha-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human alpha-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of alpha-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.

Animals↗

PubMed2001

Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's disease.

The permeability of albumin, insulin, and human A beta 1--40 at the blood-brain barrier (BBB) was determined in the normal adult mouse (B6/SJL) and in the double transgenic Alzheimer mouse (APP, PS1) by using an I.V. bolus injection technique to quantify the permeability coefficient-surface area (PS) product for each protein after correction for the residual plasma volume (V(p)) occupied by the protein in the blood vessels of different brain regions using a second aliquot of the same protein radiolabeled with a different isotope of iodine ((125)I vs (131)I) as a vascular space marker. This technology for quantifying BBB permeability of proteins was adapted from the rat to the mouse and involved catheterizing the femoral artery and vein of the mouse instead of the brachial artery and vein as for the rat. Because of the smaller blood volume in the mouse, serial sampling (20 microl) of blood from the femoral artery of the mouse was performed and directly TCA precipitated to generate a whole blood washout curve for the intact protein. When similar blood sampling techniques were used in the rat, the PS values for albumin and insulin at the BBB were similar in these two species. In the double transgenic mouse, the V(p) values for albumin were significantly increased 1.4- to 1.6-fold in five of six brain regions compared to the normal adult mouse, which indicated increased adherence of albumin to vessel walls. As a result, the PS values were significantly decreased, from 1.4- to 3.2-fold, which likely reflected decreased transport of albumin by passive diffusion. In contrast, insulin, which is taken up into the brain by a receptor-mediated transport mechanism at the BBB, showed no significant difference in the V(p) values but a significant increase in the PS values in four of six brain regions. This suggests a compensatory mechanism in the Alzheimer's transgenic brain whereby there is an increased permeability to insulin at the BBB. Surprisingly, there was no significant difference in the V(p) or PS values for human A beta 1--40 at the BBB in the double transgenic Alzheimer mouse at 24, 32, or 52 weeks of age, when there is both significant A beta levels in the plasma and amyloid burden in the brains of these animals. These data suggest that there is not an alteration in permeability to human A beta 1--40 at the BBB with increasing amyloid burden in the double transgenic Alzheimer mouse. Although these observations suggest structural alterations at the BBB, they do not support the concept of extensive BBB damage with substantial increases in BBB permeability in Alzheimer's disease.

Age Factors↗

PubMed2001

Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease.

Mutations in the amyloid precursor protein (APP) and presenilin-1 and -2 genes (PS-1, -2) cause Alzheimer's disease (AD). Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of beta-amyloid (Abeta) at an early age. In this study, we have examined how Abeta deposition is associated with immune responses. Both fibrillar and nonfibrillar Abeta (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar Abeta deposits increased up to the oldest age studied (2.5 years old), whereas there were less marked changes in the number of diffuse deposits in mice over 1 year old. Activated microglia and astrocytes increased synchronously with amyloid burden and were, in general, closely associated with deposits. Cyclooxygenase-2, an inflammatory response molecule involved in the prostaglandin pathway, was up-regulated in astrocytes associated with some fibrillar deposits. Complement component 1q, an immune response component, strongly colocalized with fibrillar Abeta, but was also up-regulated in some plaque-associated microglia. These results show: i) an increasing proportion of amyloid is composed of fibrillar Abeta in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse Abeta; and iii) cyclooxygenase-2 and complement component 1q levels increase in response to the formation of fibrillar Abeta in PS/APP mice.

Aging↗

PubMed2001

Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease.

Beta-amyloid is one of the most significant features of Alzheimer's disease, and has been considered to play a pivotal role in neurodegeneration through an unknown mechanism. However, it has been noted that beta-amyloid accumulation is associated with markers of oxidative stress including protein oxidation (Smith et al., 1997), lipid peroxidation (Mark et al., 1997; Sayre et al., 1997), advanced glycation end products (Smith et al., 1994), and oxidation of nucleic acids (Nunomura et al., 1999). Furthermore, studies from cultured cells have shown that beta-amyloid leads to an increase in hydrogen peroxide levels (Behl et al., 1994), and the production of reactive oxygen intermediates (Harris et al., 1995). Taken together, this evidence supports the idea that beta-amyloid plays a key role in oxidative stress-evoked neuropathology. In this study, we examined the induction of oxidative stress in response to amyloid load in a mouse model of Alzheimer's disease. The mice carrying mutant amyloid precursor protein and presenilins-1 (Goate et al., 1991; Hardy, 1997), develops beta-amyloid deposits at 10-12 weeks of age and show several features of the human disease (Holcomb et al., 1998; Matsuoka et al., 2001; McGowan et al., 1999; Takeuchi et al., 2000; Wong et al., 1999). Both 3-nitrotyrosine and 4-hydroxy-2-nonenal (protein and lipid oxidative stress markers, respectively) associate strongly with fibrillar beta-amyloid, but not with diffuse (thioflavine S negative) beta-amyloid, and the levels increase in relation to the age-associated increase in fibrillar amyloid load.From these data we suggest that fibrillar beta-amyloid is associated with oxidative damage which may influence disease progression in the Alzheimer's disease brain.

Aging↗

PubMed2001

Electrical injury and lightning injury: a review of their mechanisms and neuropsychological, psychiatric, and neurological sequelae.

Exposure to electrical current via industrial or residential accidents or lightning strikes is a serious and growing concern in today's medical community. The sequelae that result are referred to as electrical injury (EI) or lightning injury (LI). The relevant principles in electricity are reviewed with particular attention given to their damaging capabilities on the body. Specific neuropsychological, psychiatric, and neurological signs and symptoms as well as objective measures of psychological and neuropsychological functioning and brain imaging in victims of EI and LI, are reviewed from past research. Important issues relevant to researchers in the field are discussed. Finally, the role that neuropsychology might play in this area is outlined.

Brain Injury, Chronic↗

PubMed2001

Transgenic mouse models of Alzheimer's disease: phenotype and mechanisms of pathogenesis.

A range of transgenic mice have been created to model Alzheimer's disease. These include mice expressing human forms of the amyloid precursor protein, the presenilins and, more recently, tau. Several of the models develop features of the disease including amyloid pathology, cholinergic deficits, neurodegeneration and cognitive impairment. Progress in the characterization and use of these model animals is discussed.

Alzheimer Disease↗

PubMed2001

Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption.

Neurites that pass through amyloid-beta deposits in Alzheimer disease (AD) undergo 3 changes: they develop phosphorylated tau immunoreactivity; the density of SMI-32-positive dendrites diminishes; and they also develop a marked alteration in their geometric features, changing from being nearly straight to being quite curvy. The extent to which the latter 2 phenomena are related to phosphorylated tau is unknown. We have now examined whether amyloid-beta deposits in APP695Sw transgenic mice, which have only rare phosphorylated tau containing neurites. develop these changes. We found that dendritic density is diminished within the boundaries of amyloid-beta plaques, with the greatest loss (about 80%, p < 0.001) within the boundaries of thioflavine S cores. Remaining dendrites within plaques develop substantial morphological alterations quantitatively similar to those seen in AD. A statistically significant but smaller degree of change in geometry was seen in the immediate vicinity around plaques, suggesting a propagation of cytoskeletal disruption from the center of the plaque outward. We examined the possible physiological consequences of this change in dendritic geometry using a standard cable-theory model. We found a predicted delay of several milliseconds in about one quarter of the dendrites passing through a thioflavine S plaque. These results are consistent with previous observations in AD, and suggest that thioflavine S-positive amyloid-beta deposits have a marked effect on dendritic microarchitecture in the cortex, even in the relative absence of phosphorylated tau alterations.

Action Potentials↗

PubMed2001

Progress in the modeling of neurodegenerative diseases in transgenic mice.

Transgenic mouse models exist for the major neurodegenerative diseases, including Alzheimer's disease, tauopathy and amyotrophic lateral sclerosis. Although many of the mice do not completely replicate the human disease they are intended to model, they have provided insight into the mechanisms that underlie disease etiology. In the case of the Alzheimer's disease and amyotrophic lateral sclerosis models, the mice have also provided a therapeutic testing ground for the testing of agents that have been shown to have considerable clinical promise.

Animals↗

PubMed2001

Practice effects, test-retest stability, and dual baseline assessments with the California Verbal Learning Test in an HIV sample.

Repeated neuropsychological assessments have been recently employed to investigate the natural course and effects of interventions in individuals with human immunodeficiency virus (HIV) infection. Important considerations when interpreting serial assessments are the roles of practice effects and test-retest reliability on follow-up performance. Although several statistical and methodological controls have been proposed for minimizing practice effects, they have not been empirically tested in HIV samples. Three groups (HIV+/symptomatic, HIV+/asymptomatic, HIV- "at risk" controls) were administered the California Verbal Learning Test (CVLT) twice with a brief test-retest interval. Significant practice effects were observed on six of the CVLT measures. Test-retest stability coefficients were reported. A third and fourth administration of the CVLT was conducted to observe the impact of the dual baseline assessment approach on test performance. Trend analyses indicated that the dual baseline approach is a viable method for minimizing practice effects. The dual baseline approach also lead to improvement in a number of the stability coefficients. Limitations and future directions are discussed.

Journal Article↗

PubMed2000

Optimized stationary phases for the high-performance liquid chromatography-electrospray ionization mass spectrometric analysis of basic pharmaceuticals.

Stationary phases were investigated for HPLC coupled with electrospray ionization mass spectrometry (ESI-MS) for the analysis of basic drugs. Tricyclic antidepressants (TCAs) and beta-blockers were used as model solutes. The functional groups, pentafluorophenyl (PFP), OH, CN or CH3 were attached to the silica via a propyl chain. The effects of these stationary phases as well as C8 and C18 phases on retention and peak shape of the basic drugs were studied. The CN and PFP phases adequately retained (tR of 2 to 6 min) the basic drugs when the mobile phase was composed of 90% acetonitrile, whereas with the C4, C8 and C18 phases, less than 40% acetonitrile had to be used to provide adequate retention of the basic drugs. Because acetonitrile provides better desolvation in ESI than an aqueous solvent, it produces an increased MS signal. As an example of the HPLC-ESI-MS analysis of the beta-blocker, pindolol, on a CN phase, the use of 90% acetonitrile in the mobile phase increased the ESI-MS signal by 790% when compared to a C18 phase which could use only 5% acetonitrile in the mobile phase for retention of the solute. In addition, the CN and PFP phases provided better peak shape than the OH phase and the hydrophobic phases (C4, C8 and C18) and ion-pairing or ion-suppressing agents were not required. The retention behavior of the TCAs and beta-blockers on each of the phases is described.

Adrenergic beta-Antagonists↗

PubMed2000

Functional phenotype in transgenic mice expressing mutant human presenilin-1.

Mutations in the presenilin-1 (PS1) gene cause approximately 50% of cases of early onset familial Alzheimer's disease. The function of this protein remains unknown. We have made an electrophysiological study of hippocampal slices from transgenic mice expressing either a normal human PS1 transgene (WT) or one of two human PS1 transgenes bearing pathogenic mutations at codon M146 (M146L and M146V). Medium and late afterhyperpolarizations in CA3 pyramidal cells were larger in mice expressing either mutant form compared with WT and nontransgenic controls. Calcium responses to depolarization were larger in M146L mice compared with nontransgenic littermates; synaptic potentiation of the CA3 to CA1 projection was also stronger. These results demonstrate disruption of the control of intracellular calcium and electrophysiological dysfunction in PS1 mutant mice.

Alzheimer Disease↗

PubMed2000

Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes.

To examine the normal cellular function of tau and its role in pathogenesis, we have created transgenic mice that overexpress a tau transgene derived from a human PAC that contains the coding sequence, intronic regions, and regulatory regions of the human gene. All six isoforms of human tau are represented in the transgenic mouse brain at the mRNA and protein level and the human tau is distributed in neurites and at synapses, but is absent from cell bodies. A comparison between the genomic tau mice and mice that overexpress a tau cDNA transgene shows that overall, the distribution of tau is similar in the two lines, but human tau is located in the somatodendritic compartment of many neurons in the cDNA mice. Tau-immunoreactive axonal swellings were found in the spinal cords of the cDNA mice, which correlated with a hind-limb abnormality, whereas neuropathology was essentially normal in the genomic mice up to 8 months of age.

Alzheimer Disease↗