Ausma Rabe
University of Michigan, Psychobiology, Emeritus
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The development, function and maintenance of the central nervous system (CNS) tissue are regulated in a timed sequence of inductions by growth factors (GF) and neuroactive amino acids (NAA)16. Taurine in particular has been identified as... more
The development, function and maintenance of the central nervous system (CNS) tissue are regulated in a timed sequence of inductions by growth factors (GF) and neuroactive amino acids (NAA)16. Taurine in particular has been identified as a “balancing factor” in the glutamate system to modulate and stabilize calcium homeostasis or enantiostasis and thus calcium-dependent cellular functions (for reviews22,44,50,48).
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Our previous study showed an improvement in locomotor deficits after voluntary lifelong running in Ts65Dn mice, an animal model for Down syndrome (DS). In the present study, we employed mouse microarrays printed with 55,681 probes in an... more
Our previous study showed an improvement in locomotor deficits after voluntary lifelong running in Ts65Dn mice, an animal model for Down syndrome (DS). In the present study, we employed mouse microarrays printed with 55,681 probes in an attempt to identify molecular changes in the cerebellar transcriptome that might contribute to the observed behavioral benefits of voluntary long-term running in Ts65Dn mice. Euploid mice were processed in parallel for comparative purposes in some analyses. We found that running significantly changed the expression of 4,315 genes in the cerebellum of Ts65Dn mice, over five times more than in euploid animals, up-regulating 1,991 and down-regulating 2,324 genes. Functional analysis of these genes revealed a significant enrichment of 92 terms in the biological process category, including regulation of biosynthesis and metabolism, protein modification, phosphate metabolism, synaptic transmission, development, regulation of cell death/apoptosis, protein t...
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Publisher Summary This chapter discusses approach for discovering conditions under which normal fetal tissue transplanted into infant brains could ameliorate impaired function resulting from congenital brain defects. The approach is... more
Publisher Summary This chapter discusses approach for discovering conditions under which normal fetal tissue transplanted into infant brains could ameliorate impaired function resulting from congenital brain defects. The approach is unique in 2 respects: (1) by adding new rather than replacing lost tissue, it improves the function of the host brain beyond its intrinsic capacity and (2) functional effects are assessed at maturity and in old age, even though transplants are sustained in infancy. The effect of transplants on some of the impaired behaviors is described in the chapter. In the approach described in the chapter, although the transplant was structurally well integrated into the host brain, its presence reduced neither the hyperactivity of micrencephalic rats in an open field nor the deficit they display in learning a multiple choice water maze. Both tests were done at 2 months and one year after transplantation. Electrophysiological recordings of electroencephalography and visual evoked potentials (VEP) obtained from young adult transplant-bearing micrencephalic rats have been more encouraging. Salutary transplant effects were also observed with two different behavioral tests given at older ages, a visual pattern discrimination test and spatial navigation.
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Research Interests: Psychology, Cognitive Science, Aging, Medicine, Swimming, and 9 moreLearning, Brain, Female, Animals, Male, Rats, Time Factors, Body Weight, and Neurosciences
Down’s syndrome (DS), or trisomy 21, is a major known cause of mental retardation, occurring in 1 of every 1000 live births.1 Alzheimer’s disease (AD) is a progressive dementing disorder, with characteristic brain pathology, that affects... more
Down’s syndrome (DS), or trisomy 21, is a major known cause of mental retardation, occurring in 1 of every 1000 live births.1 Alzheimer’s disease (AD) is a progressive dementing disorder, with characteristic brain pathology, that affects about 10% of people over 65 years of age.2 3 The presence of Alzheimer-type pathology in the brains of almost all people 35 years and older with DS has been the cornerstone for the widely held view that people with DS will develop AD not only at a much younger age, but also in much larger numbers than will people without DS.4-7 Because of this relationship between DS and AD, it has been widely assumed that knowledge about almost any aspect of one of these conditions will illuminate the other.8-11 For example, the similarity of the morphological and neurochemical abnormalities in AD and DS has led to the proposition that aging DS brains may serve as a model for the pathogenesis of brain abnormalities in AD.12 13 In addition, since DS is a genetic disorder with many features of premature aging,14 it has been expected that the study of DS will contribute important information about the role of genetics and aging in the etiology of AD.15-19
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Research Interests: Learning, Memory, Hippocampus, Learning and Memory, Mice, and 15 moreBlood brain barrier, Female, Animals, Male, LIFR, Differentiation, Clinical Sciences, Dentate Gyrus, Neural Progenitor Cells, Neural Stem Cells, Cell Proliferation, Biological activity, Leukemia Inhibitory Factor, Ciliary Neurotrophic Factor, and Morris water maze
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Research Interests: Neuroscience, Psychology, Biology, Medicine, Down Syndrome, and 14 moreTransgenic Mice, Cell Differentiation, Mice, Animals, Trisomy 21, Time Factors, Glial Fibrillary Acidic Protein, Neural Stem Cells, Mosaicism, Harmine, Neurosciences, Glutamate decarboxylase, Protein tyrosine kinases, and Monoamine oxidase inhibitors
The gene encoding dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is located within the Down syndrome (DS) critical region of chromosome 21. DYRK1A interacts with a plethora of substrates in the cytosol,... more
The gene encoding dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is located within the Down syndrome (DS) critical region of chromosome 21. DYRK1A interacts with a plethora of substrates in the cytosol, cytoskeleton, and nucleus. Its overexpression is a contributing factor to the developmental alterations and age-associated pathology observed in DS. We hypothesized that the intracellular distribution of DYRK1A and cell-compartment-specific functions are associated with DYRK1A posttranslational modifications. Fractionation showed that, in both human and mouse brain, almost 80% of DYRK1A was associated with the cytoskeleton, and the remaining DYRK1A was present in the cytosolic and nuclear fractions. Coimmunoprecipitation revealed that DYRK1A in the brain cytoskeleton fraction forms complexes with filamentous actin, neurofilaments, and tubulin. Two-dimensional gel analysis of the fractions revealed DYRK1A with distinct isoelectric points: 5.5-6.5 in the nucleus, 7.2-8.2 in the cytoskeleton, and 8.7 in the cytosol. Phosphate-affinity gel electrophoresis demonstrated several bands of DYRK1A with different mobility shifts for nuclear, cytoskeletal, and cytosolic DYRK1A, indicating modification by phosphorylation. Mass spectrometry analysis disclosed one phosphorylated site in the cytosolic DYRK1A and multiple phosphorylated residues in the cytoskeletal DYRK1A, including two not previously described. This study supports the hypothesis that intracellular distribution and compartment-specific functions of DYRK1A may depend on its phosphorylation pattern.
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Normal fetal (E18) neocortical tissue transplanted into the hypoplastic posterior neocortex of infant (10 +/- 2-day-old) rats with transplacentally induced micrencephaly developed into very large, healthy, and permanent transplants.... more
Normal fetal (E18) neocortical tissue transplanted into the hypoplastic posterior neocortex of infant (10 +/- 2-day-old) rats with transplacentally induced micrencephaly developed into very large, healthy, and permanent transplants. Although the cellular organization within the transplants rarely resembled that of normal rat neocortex, the transplants formed a broad area of interface with the host brain and established fiber connections with it. When tested at 2 months and 1-year-of-age, the presence of the transplant had no significant effect on the typically abnormal performance of micrencephalic rats on two tests of unspecific function, open field activity and maze learning. However, a small group of micrencephalic rats in whom the transplant tissue had failed to fill in the small brain lesions inescapably inflicted during surgery, showed greater behavioral deficits than the micrencephalic controls, suggesting that the transplant had corrected the lesion effect.
Research Interests: Pathology, Cognitive Science, Animal Behavior, Behavior, Biology, and 11 moreMedicine, Brain, Cerebral Cortex, Female, Animals, Male, Exploration, Rats, Foetus, Fetus, and Neurosciences
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Long-Evans rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate and normal controls were trained in a two-choice box to discriminate between stimuli of different brightness (black vs. white) or pattern... more
Long-Evans rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate and normal controls were trained in a two-choice box to discriminate between stimuli of different brightness (black vs. white) or pattern (horizontal vs. vertical alternating black-and-white stripes). Mild footshock was used to motivate the rats to learn. The micrencephalic rats were impaired in learning the pattern, but not brightness discrimination. These results confirm and extend similar findings with micrencephalic Wistar rats by another laboratory. The visual discrimination performance of micrencephalic rats was similar to that reported for normal rats with lesions in the visual cortical areas.
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The involvement of blood microvessels, representing the anatomic site of the blood-brain barrier (BBB), in brain damage induced by prenatal exposure to lipopolysaccharide (LPS) and/or valproic acid (VPA) was studied in four-week-old rats.... more
The involvement of blood microvessels, representing the anatomic site of the blood-brain barrier (BBB), in brain damage induced by prenatal exposure to lipopolysaccharide (LPS) and/or valproic acid (VPA) was studied in four-week-old rats. The immunogold procedure was applied for localization at the ultrastructural level of endogenous albumin and glucose transporter (GLUT-1) in three brain regions: cerebral cortex, cerebellum and hippocampus. Four groups of rats were used: (1) untreated control, (2) prenatally VPA-treated, (3) prenatally LPS-treated, and (4) prenatally LPS- and VPA-treated. The functional state of the BBB was evaluated as follows: (a) by its tightness, i.e., permeability to blood-borne albumin, and (b) by the expression of GLUT-1 in the endothelial cells (ECs). Using morphometry, the labelling density for GLUT-1 was recorded over luminal and abluminal plasma membranes of the ECs, also providing information on their functional polarity. No extensive increase of vascular permeability and/or any considerable dysfunction of the BBB in experimental groups nos. 2 and 3 were observed, although in solitary vascular profiles, increased endocytosis or even transcytosis of albumin by ECs was noted. In experimental group no. 4, some vascular profiles showed scanty leakage (microleakage), manifested by the presence of immunosignals for albumin in the perivascular area. Although some fluctuations in the expression of GLUT-1 occurred in all experimental groups, especially in group no. 3, a most pronounced and significant diminution of the labelling density, in all three regions of the brain, was observed in group no. 4. This finding suggests the synergistic action of prenatally applied LPS and VPA that affects specific transport functions of glucose in the microvascular endothelium. The diminished or disturbed supply of glucose to selected brain regions can be one of the factors leading to previously observed behavioral disturbances in similarly treated rats.
Research Interests: Microcirculation, Immunohistochemistry, Enzyme Inhibitors, Transmission Electron Microscopy, Intellectual Disability, and 20 morePregnancy, Humans, Child, Glucose, Endothelial Cells, Endocytosis, Blood brain barrier, Female, Animals, Developmental disabilities, Brain Ischemia, Glucose Transport, Lipopolysaccharides, Rats, Valproic Acid, Endothelial cell, Vascular Permeability, Neurosciences, Biochemistry and cell biology, and Cell Membrane
The unequivocal diagnosis of Alzheimer disease (AD) rests on histopathological evidence at brain autopsy or biopsy. Although the histological features of AD are well known, defining criteria for the morphological diagnosis of AD is... more
The unequivocal diagnosis of Alzheimer disease (AD) rests on histopathological evidence at brain autopsy or biopsy. Although the histological features of AD are well known, defining criteria for the morphological diagnosis of AD is difficult due to the phenotypical heterogeneity of the disease, absence of specific markers, and overlap of AD pathology with that observed in non-demented elderly individuals. This gray zone between normal to pathological aging and full-fledged AD represents an important diagnostic problem and should be overcome by better standardized criteria that will allow to minimize interrater and interlaboratory variability in the diagnosis of AD. Current criteria for the neuropathological diagnosis of AD are based on age-related (semi)quantitative assessment of "senile" plaques (NIA criteria), neuritic plaques (CERAD), plaques and neurofibrillary tangles in neocortex and hippocampus (Tierney et al., 1988), and staging of hierarchic spreading of neuritic AD changes in particular, neurofibrillary tangles (Braak and Braak, 1991). All these algorithms have some weaknesses and do not recognize the various subtypes of AD. Multivariant analysis of an autopsy series of elderly subjects revealed significant correlations between psychostatus assessed by the Mini-Mental State and both the CERAD criteria and Braak staging. Although the role of plaques and tangles in the pathogenesis of AD and their relationship to both neuronal loss and dementia remain to be elucidated, clinicopathological studies have shown that both lesions, if present in sufficient numbers, particularly in the neocortex, are considered the best correlates for AD related dementia. Recent consensus recommendations of the NIA- and Reagan Institute Working Group for the morphological diagnosis of AD consider AD as a heterogenous clinicopathological entity. After exclusion of other causes of dementia, the likelihood that AD accounts for dementia is considered high, intermediate or low according to the frequency of neuritic AD lesions with regard to both the CERAD criteria and Braak staging. The evaluation of small autopsy series according to these criteria demonstrated their easy and rapid application in AD and non-demented subjects, with much less reliability for other dementing disorders.
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Two satisfactory rat models of maternal phenylketonuria (PKU) have been developed. Continuous subcutaneous infusion into pregnant rats from the 9th-20th day of gestation of either (1) phenylacetate (PA), to elevate plasma levels of... more
Two satisfactory rat models of maternal phenylketonuria (PKU) have been developed. Continuous subcutaneous infusion into pregnant rats from the 9th-20th day of gestation of either (1) phenylacetate (PA), to elevate plasma levels of unconjugated PA to 0.25-0.60 mumol/ml, or (2) a nontoxic dose (0.2 mumol/g/day) of p-chlorophenylalanine (pClPhe) with L-phenylalanine (Phe), to elevate plasma Phe levels at least 10-fold (1.7-2.3 mumol/ml) and unconjugated PA to at least 0.2 mumol/ml, produced the syndrome of untreated maternal PKU: spontaneous abortion, mortality rate greater than normal among the newborn, retarded growth of fetal body and brain, and a learning deficit among the progeny. From the plasma of rats infused with only pClPhe, a metabolite was isolated and identified as p-chlorophenylacetic acid. This compound, at a concentration greater than 0.15 mumol/ml plasma was found to retard fetal body and brain growth. In the pregnant rat, plasma levels of unconjugated PA, in the range observed in some PKU individuals on a normal diet, effectively induced a simulation of maternal PKU. The results of this investigation support our contention that PA, which is produced in excessive amounts in clinical PKU, is the primary cause of the brain dysfunction.
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Research Interests: Multidisciplinary, Down Syndrome, Brain, Humans, Aged, and 3 moreMiddle Aged, Adult, and Alzheimer Disease
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Research Interests: Cognitive Science, Aging, Memory, Pregnancy, Mice, and 7 moreFemale, Animals, Male, Ethanol, Maze Learning, Neurosciences, and Maternal-fetal exchange
Rats with bilateral anterior and posterior hippocampal lesions (APH), anterior hippocampal lesions (AH), and controls were trained on CRF for water, and then switched to FR-20. Both hippocampal groups adapted more readily than controls to... more
Rats with bilateral anterior and posterior hippocampal lesions (APH), anterior hippocampal lesions (AH), and controls were trained on CRF for water, and then switched to FR-20. Both hippocampal groups adapted more readily than controls to the FR-20 schedule and maintained significantly higher rates for 45 days. There were no significant differences on FR-20 between the lesion groups. Following FR-20, the rates of all groups were equalized by training on FR-30. During subsequent extinction, the APH group made significantly more responses than both the AH and control groups, while AH and control groups were indistinguishable. The acquisition results were interpreted as indicating increased emotional reactivity to delay of anticipated reward in both hippocampally lesioned groups. The extinction results suggested that APH, but not AH, lesions also result in increased perseveration.
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The densities of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed quantitatively in the brains of 303 mentally retarded adults 23 to 90 years of age at the time of their deaths (mean=59.5 years). Cases with Down's... more
The densities of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed quantitatively in the brains of 303 mentally retarded adults 23 to 90 years of age at the time of their deaths (mean=59.5 years). Cases with Down's syndrome, hydrocephalus and metabolic disorders were excluded from the study. Examinations of frontal, temporal, parietal, and occipital cortex, as well as hippocampus and parahippocampal gyrus were made in every case. NPs and/or NFTs were observed within the brains of 163 cases (53.8%). Detailed analyses indicated that NP density within all brain regions examined was positively related to age, with the largest age associated increases in density seen in frontal and temporal regions. In contrast, NFT density increased with age only within hippocampus and parahippocampal gyrus, but not neocortex. In addition, NP lesions within neocortex were more diffusely distributed across regions for older compared to younger cases, while no similar age-associated change in the topography of NFTs was observed. Finally, factor analyses of the combined NP and NFT data indicated that, while strong correlations existed across the various brain regions for measures of NP and NFT densities, considered separately, there was virtually no indication of regional associations between these two types of lesions. While these data, from cases with mental retardation, cannot be generalized directly to the nonretarded population, they provide strong evidence that models of Alzheimer pathogenesis must take into account the fact that regional densities of NPs and NFTs, and, therefore, the underlying processes associated with formation of these lesions, can be largely independent.
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Distribution of glucose transporter (GLUT-1) in brain microvascular endothelium, representing the anatomic site of the blood-brain barrier (BBB), was studied with electron microscopy in 24-month-old mice, which had been exposed prenatally... more
Distribution of glucose transporter (GLUT-1) in brain microvascular endothelium, representing the anatomic site of the blood-brain barrier (BBB), was studied with electron microscopy in 24-month-old mice, which had been exposed prenatally (on 9th day of gestation) to a single teratogenic dose of ethanol. Offspring of mice that had received an equivalent volume of isocaloric dextrose served as controls. Sections of brain samples embedded at low temperature in hydrophilic resin Lowicryl K4M were exposed to anti-GLUT-1 antiserum followed by gold-labelled secondary antibodies. By using morphometry, the labelling density was recorded over luminal and abluminal plasma membranes of the endothelial cells of blood microvessels supplying four brain regions: cortex, hippocampus, cerebellum and olfactory bulb. We found that the density of immunosignals for GLUT-1, represented by colloidal gold particles, was unchanged in the olfactory bulb and slightly lowered in the abluminal plasmalemma of the vascular endothelium in the cerebral cortex of the ethanol-treated mice. In contrast, statistical analysis using Mann-Whitney U-test revealed that in the hippocampus and cerebellum, the density of immunolabelling of both plasma membranes of microvascular endothelial cells was significantly lowered in the ethanol-treated mice. These findings suggest that prenatally applied ethanol had a different influence on the vasculature supplying different brain regions. In effect, the inefficient supply of glucose to selected brain regions can be one of the factors leading to the previously observed deficit in long-term memory in a similar alcohol-treated group of mice.
Research Interests: Electron Microscopy, Statistical Analysis, Aging, Microcirculation, Immunohistochemistry, and 20 moreBrain, Pregnancy, Cerebral Cortex, Mice, Blood brain barrier, Female, Animals, Male, Ethanol, Vascular endothelium, Glucose Transport, Endothelial cell, Long Term Memory, Olfactory Bulb, Low Temperature, Teratogens, Neurosciences, Plasma Membrane, Colloidal Gold, and Biochemistry and cell biology
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... 76, 441-446 (1982) RESEARCH NOTE Learning Deficit in Immature Rabbits with Aluminum-Induced Neurofibrillary Changes AUSMA RABE, MOON HE LEE, JUDY SHEK, AND ... In SDAT, they are made of paired, round 10-nm helically wound filaments... more
... 76, 441-446 (1982) RESEARCH NOTE Learning Deficit in Immature Rabbits with Aluminum-Induced Neurofibrillary Changes AUSMA RABE, MOON HE LEE, JUDY SHEK, AND ... In SDAT, they are made of paired, round 10-nm helically wound filaments with a twist every 80 ...
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Fischer rats injected with methylazoxymethanol late in pregnancy produce young with considerably reduced cerebral hemispheres. They appear normal otherwise. As adults these animals make many more errors in the Hebb-Williams maze than do... more
Fischer rats injected with methylazoxymethanol late in pregnancy produce young with considerably reduced cerebral hemispheres. They appear normal otherwise. As adults these animals make many more errors in the Hebb-Williams maze than do control animals.