M. Paranthaman, A. Manthiram and JB Goodenough, J. Solid State Chem. 87 (1990), p. 371. ... IM Ko... more M. Paranthaman, A. Manthiram and JB Goodenough, J. Solid State Chem. 87 (1990), p. 371. ... IM Koltoff and R. Belcher, Volumetric Analysis-111, Interscience, New York (1957), p. 371. ... EH Appolman, LR Morss, AM Kini, U. Geiser, A. Umezawa, GW Crabtree and KD ...
Journal of Biomedical Materials Research Part A, 2012
A simple and cost effective dip coating method was used to deposit thin films of amorphous (AM) o... more A simple and cost effective dip coating method was used to deposit thin films of amorphous (AM) or anatase (AN) titanium dioxide (TiO 2) on borosilicate glass substrates, either with or without prior doping of TiO 2 with nickel (Ni) cations by a specially designed sol gel technique. The objective of the study was to compare the physicochemical and biological properties of these films and assess their use in orthopedic implants or for in vitro cell biological studies. Analytical techniques such as XRD and XPS, in combination with ATR-FTIR and SEM revealed that only AN films, prepared by controlled heating up to 450 C, irrespective of prior doping with Ni, contained significant crystalline structures of variable morphologies. This observation could be linked to the carbon and oxygen contents and the availability of functional groups in the films. Cell biological studies revealed that Ni doping of TiO 2 in both AM and AN films improved the adhesion, spreading, proliferation, differentiation, and migration of MC3T3 cells. Our studies provide a new approach to prepare optically transparent metal surfaces, with tunable physicochemical properties, which could be suitable for eliciting optimal osteoinductive cell responses and permit the detailed in vitro cell biological studies of osteoblasts. V
Undoped and manganese ion-doped TiO 2 powders and thin films have been prepared by sol-gel route.... more Undoped and manganese ion-doped TiO 2 powders and thin films have been prepared by sol-gel route. The concentration of the manganese in TiO 2 powders and films varied from 2 to 10 mol%. These powders were annealed at different temperatures from 300 to 1000 8C while films were annealed at 450 8C for 1 h. Prepared samples were characterized by XRD, SEM, XPS, spectroscopic and contact angle measurement techniques. Photocatalytic activity, in terms of rate constant measured by degradation of methylene blue dye, under UV exposure was found to increase from 0.27 to 0.36 for 5 mol% doping while very small photo activity has been observed under visible light exposure. Hydrophillicity also shows the same behavior. Optical studies revealed the generation of allowed energy band in the forbidden gap at $0.63 eV below the conduction band. It has been concluded that Mn doping increases photocatalytic activity by scavenging the photogenerated electrons, thereby increasing the life time of charge carriers and increasing the exposed surface area by reducing the crystallite size.
Fruhere Studien weisen auf verschiedene Arten von visuellen Storungen bei der Alzheimer’schen Kra... more Fruhere Studien weisen auf verschiedene Arten von visuellen Storungen bei der Alzheimer’schen Krankheit (ALZ), die sich in Defizienzen in der Kontrastempfindlichkeit, der Stereosehscharfe, der Farben- und Formerkennung und der visuospatialen Orientierung ausdrucken [1–3]. Diese Storungen werden vor allem durch degenerative Veranderungen im visuellen Kortex [1,3] erklart, wahrend die retinocalcarine Funktion relativ gut erhalten bleibt [4]. Nun wurde aber eine alternative Hypothese vorgeschlagen, indem eine Deafferentierung vom primaren visuellen Kortex die Folge einer selektiven Degeneration und eines Verlustes von grosen Ganglienzellen der Retina und von optischen Nervenfasern sein konnte [5, 6]. Als wichtigste Merkmale in der ALZ sind die senile Plaques (SP), mit oder ohne neuritischer Komponente, die neurofibrillaren Knauel (neurofibrillary tangles (NFT)) und neuronaler Verlust [7] zu nennen. Wir haben eine morphologische Studie auf drei Ebenen des visuellen Systems bei der ALZ unternommen: im primaren und sekundaren visuellen Kortex (Areae 17 und 18), im lateralen Nucleus geniculatus (LNG) und im Colliculus superior (CS). Nahere Einzelheiten zur Methode und den Ergebnissen sind anderswo beschrieben [8, 9].
We generated defined neuronal loss in hippocampus of genetically identical mice by pilocarpine in... more We generated defined neuronal loss in hippocampus of genetically identical mice by pilocarpine injections and studied the impact of these seizures on the performance of mice in spatial learning and memory. The numbers of TUNEL-positive degenerating cells paralleled the severity of the seizures. When compared to the numbers found for not-seizured control mice, mild, moderate, and severe seizures produced significant increases in TUNEL-positive neurons in CA1 and CA3 regions by 19, 25, and 63%, respectively. Water maze learning was abolished after the severe seizures. However, spatial learning was normal after mild or moderate seizures. Therefore, there was no linear correlation between the impairment of learning and memory performance with the number of degenerating neurons in hippocampus. Our data suggest that normal spatial learning and memory can be achieved without the full number of hippocampal pyramidal neurons in partially lesioned hippocampus.
potential to spontaneously induce amyloid plaque formation m l~iti-0 under various expenmental co... more potential to spontaneously induce amyloid plaque formation m l~iti-0 under various expenmental conditions. 'The resulta demonstrated that hepariniheparan wlfate GAGS, heparan sulfate-containmg proteoglycans, and related highly sulfated macromolecules effectively induce spontaneous amyloid plaque formation (i.e. maltesecross amyloid-star plaques) in a test tube under the appropriate experimental condmons. Transmission and scanning electron microscopy indicated that such artificially produced amyloid plaqucs were virtually morphologically identical to human amyloid plaques isolated from AD brain. The discovery that highly wlfated GAGS induce spontaneous amyloid plaque formation in rirm further implicates their role m the pathogeneaia of AD leslon development.
The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimer's disease (AD). We h... more The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimer's disease (AD). We have generated transgenic mice expressing BACE and double transgenic mice expressing BACE and the Swedish mutations of APP (SwAPP) in neurons. BACE transgenic mice did not develop bamyloid plaques by age of 14 months, but showed intracellular b-amyloid immunoreactivity that was co-localized with transgenic BACE in neurons. Ab levels were increased and AD-like pathology was accelerated in double transgenic mice expressing both BACE and SwAPP. At two months of age, early signs of extracellular Ab deposition and reactive astrocytes were found in double transgenic, but not in single transgenic mice. Furthermore, at four months, well defined b-amyloid deposits surrounded by activated astrocytes could be detected in the double transgenic mice. We suggest that BACE overexpression is not sufficient to produce b-amyloid plaques, but simultaneous expression of BACE and its substrate (SwAPP) leads to an accelerated amyloid plaque formation.
To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyl... more To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyloid precursor protein (SwAPP) on the vulnerability of central nervous system neurons, we induced epileptic seizures in transgenic mice expressing SwAPP. The transgene expression did not change the seizure threshold, but consistently more neurons degenerated in brains of SwAPP mice as compared with wild-type littermates. The degenerating neurons were stained both by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and by Gallyas silver impregnation. A susceptible population of neurons accumulated intracellular A and immunoreacted with antibodies against activated caspase-3. To demonstrate that increased A levels mediated the increased vulnerability, we infused antibodies against A and found a significant reduction in neuronal loss that was paralleled by decreased brain levels of A. Because the SwAPP mice exhibited no amyloid plaques at the age of these experiments, transgenic overproduction of A in brain rendered neurons susceptible to damage much earlier than the onset of amyloid plaque formation. Our data underscore the possibility that A is toxic, that it increases the vulnerability of neurons to excitotoxic events produced by seizures, and that lowering A by passive immunization can protect neurons from A-related toxicity. Alzheimer's disease (AD) 1 is the most common cause of dementia in the elderly. Both familial and sporadic cases share the deposition in brain of extracellular -amyloid plaques as a common pathological hallmark. -Amyloid is associated with the formation of neurofibrillary tangles, impaired synaptic functions, and the loss of neurons (1-4). -Amyloid deposits are composed of amyloid- peptides (A) that aggregate to form amyloid fibrils (5). Increased generation of the highly amyloidogenic 42-residue form (A 42) is associated with most, if not all, mutations that cause familial AD (6-12). In AD patients
We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the... more We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies.
Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau ge... more Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau gene located on chromosome 17 has been shown to be implicated in the pathogenesis of several FTD families with parkinsonism, the so called FTDP-17 families. The mutations reported so far are located within exons 9 to 13, a region coding for the microtubule-binding sites. They are causing various cytoskeletal disturbances. We are describing here the main clinical and neuropathological features of a Swiss FTD family with members presenting a FTDP-like clinical phenotype. However, if we except two silent polymorphic sites at position 227 and 255 in exon 9, neither a known FTDP-17 mutation nor a novel one was detected in this region of the tau gene. Thus, the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family. A mutation in another gene is still possible. 2000 Academic Press
The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons ... more The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons was studied with the help of an image analysis system (Vidas/Zeiss) in the primary visual area 17 and associative area 18 (Brodmann) of Alzheimer and control brains. In neither of these areas was there a significant difference between Alzheimer and control groups in the mean number of PV, CR, or CB immunoreactive neuronal profiles, counted in a cortical column going from pia to white matter. Significant differences in the mean densities (numbers per square millimeter of cortex) of PV, CR, and CB immunoreactive neuronal profiles were not observed either between groups or areas, but only between superficial, middle, and deep layers within areas 17 and 18. The optical density of the immunoreactive neuropil was also similar in Alzheimer and controls, correlating with the numerical density of immunoreactive profiles in superficial, middle, and deep layers. The frequency distribution of neuronal areas indicated significant differences between PV, CR, and CB immunoreactive neuronal profiles in both areas 17 and 18, with more large PV than CR and CB positive profiles. There were also significantly more small and less large PV and CR immunoreactive neuronal profiles in Alzheimer than in controls. Our data show that, although the brain pathology is moderate to severe, there is no prominent decrease of PV, CR and CB positive neurons in the visual cortex of Alzheimer brains, but only selective changes in neuronal perikarya. 1998 Academic Press
In this study, we quantitatively investigated the expression of β-site amyloid precursor protein ... more In this study, we quantitatively investigated the expression of β-site amyloid precursor protein cleaving enzyme (BACE) in the entorhinohippocampal and frontal cortex of Alzheimer’s disease (AD) and old control subjects. The semiquantitative estimation indicated that the intensity of BACE overall immunoreactivity did not differ significantly between AD and controls, but that a significantly stronger staining was observed in the hippocampal regions CA3–4 compared to other regions in both AD patients and controls. The quantitative estimation confirmed that the number of BACE-positive neuronal profiles was not significantly decreased in AD. However, some degeneration of BACE-positive profiles was attested by the colocalization of neurons expressing BACE and exhibiting neurofibrillary tangles (NFT), as well as by a decrease in the surface area of BACE-positive profiles. In addition, BACE immunocytochemical expression was observed in and around senile plaques (SP), as well as in reactive...
In order to study the patterns of Alzheimer disease (AD)-related pathology in the primary visual ... more In order to study the patterns of Alzheimer disease (AD)-related pathology in the primary visual system of the oldest old, we performed a quantitative analysis of senile plaques (SP), diffuse β amyloid (Aβ) deposit and neurofibrillary tangle (NFT) distribution in primary area 17, and a semi-quantitative analysis in the dorsal lateral geniculate nucleus (LGN), lateral inferior pulvinar (LIP) and superior colliculus (SC) of 21 individuals aged between 93 and 102 years. Among them, 10 cases were considered as non-demented (ND), while 9 presented very mild cognitive impairment (VMCI), and 2 cases had a clinical diagnosis of AD. Silver methenamine and Gallyas staining, Aβ and tau immunostaining revealed the distribution of AD lesions. In primary area 17, most cases, either ND or with VMCI displayed a low to medium number of SP. There was no significant difference in SP and Aβ deposit densities between ND and VMCI groups. On the whole, 0.4–2.4% of the cross-sectional cortical area was cov...
In order to understand relationships between executive and structural deficits in the frontal cor... more In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer's disease, we studied frontal pathological changes in young and old controls compared to cases with sporadic (AD) or familial Alzheimer's disease (FAD). We performed a semi-automatic computer assisted analysis of the distribution of beta-amyloid (Abeta) deposits revealed by Abeta immunostaining as well as of neurofibrillary tangles (NFT) revealed by Gallyas silver staining in Brodman areas 10 (frontal polar), 12 (ventro-infero-median) and 24 (anterior cingular), using tissue samples from 5 FAD, 6 sporadic AD and 10 control brains. We also performed densitometric measurements of glial fibrillary acidic protein, principal compound of intermediate filaments of astrocytes, and of phosphorylated neurofilament H and M epitopes in areas 10 and 24. All regions studied seem almost completely spared in normal old controls, with only the oldest ones exhibiting a weak percentage of beta-amyloid deposit and hardly any NFT. On the contrary, all AD and FAD cases were severely damaged as shown by statistically significant increased percentages of beta-amyloid deposit, as well as by a high number of NFT. FAD cases (all from the same family) had statistically more beta-amyloid and GFAP than sporadic AD cases in both areas 10 and 24 and statistically more NFT only in area 24. The correlation between the percentage of beta-amyloid and the number of NFT was significant only for area 24. Altogether, these data suggest that the frontal cortex can be spared by AD type lesions in normal aging, but is severely damaged in sporadic and still more in familial Alzheimer's disease. The frontal regions appear to be differentially vulnerable, with area 12 having the less amyloid burden, area 24 the less NFT and area 10 having both more amyloid and more NFT. This pattern of damage in frontal regions may represent a strong neuroanatomical support for the deterioration of attention and cognitive capacities as well as for the presence of emotional and behavioral troubles in AD patients.
Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that... more Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases. However, most FTD families have no demonstrable tau mutations. Here we describe the clinical and neuropathological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod score 3.46, θ ⍧ 0 for marker D17S950), but mutations in the tau gene were not found. Clinical symptoms, neuropsychological deficits and neuroimaging findings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and decreased spontaneous speech as the most prominent presenting symptoms. Pathological examination of the Keywords: familial frontotemporal dementia; FTDP-17; ubiquitin-positive inclusions Abbreviations: FTD ϭ frontotemporal dementia; FTDP-17 ϭ frontotemporal dementia and parkinsonism linked to chromosome 17; GFAP ϭ glial fibrillary acidic protein; HMPAO ϭ 99mTc-hexamethyl propyleneamine oxime; IBZM ϭ [ 123 I]iodobenzamide; MC ϭ monoclonal; PC ϭ polyclonal; RT-PCR ϭ reverse transcriptase-polymerase chain reaction; SPECT ϭ single photon emission computed tomography
M. Paranthaman, A. Manthiram and JB Goodenough, J. Solid State Chem. 87 (1990), p. 371. ... IM Ko... more M. Paranthaman, A. Manthiram and JB Goodenough, J. Solid State Chem. 87 (1990), p. 371. ... IM Koltoff and R. Belcher, Volumetric Analysis-111, Interscience, New York (1957), p. 371. ... EH Appolman, LR Morss, AM Kini, U. Geiser, A. Umezawa, GW Crabtree and KD ...
Journal of Biomedical Materials Research Part A, 2012
A simple and cost effective dip coating method was used to deposit thin films of amorphous (AM) o... more A simple and cost effective dip coating method was used to deposit thin films of amorphous (AM) or anatase (AN) titanium dioxide (TiO 2) on borosilicate glass substrates, either with or without prior doping of TiO 2 with nickel (Ni) cations by a specially designed sol gel technique. The objective of the study was to compare the physicochemical and biological properties of these films and assess their use in orthopedic implants or for in vitro cell biological studies. Analytical techniques such as XRD and XPS, in combination with ATR-FTIR and SEM revealed that only AN films, prepared by controlled heating up to 450 C, irrespective of prior doping with Ni, contained significant crystalline structures of variable morphologies. This observation could be linked to the carbon and oxygen contents and the availability of functional groups in the films. Cell biological studies revealed that Ni doping of TiO 2 in both AM and AN films improved the adhesion, spreading, proliferation, differentiation, and migration of MC3T3 cells. Our studies provide a new approach to prepare optically transparent metal surfaces, with tunable physicochemical properties, which could be suitable for eliciting optimal osteoinductive cell responses and permit the detailed in vitro cell biological studies of osteoblasts. V
Undoped and manganese ion-doped TiO 2 powders and thin films have been prepared by sol-gel route.... more Undoped and manganese ion-doped TiO 2 powders and thin films have been prepared by sol-gel route. The concentration of the manganese in TiO 2 powders and films varied from 2 to 10 mol%. These powders were annealed at different temperatures from 300 to 1000 8C while films were annealed at 450 8C for 1 h. Prepared samples were characterized by XRD, SEM, XPS, spectroscopic and contact angle measurement techniques. Photocatalytic activity, in terms of rate constant measured by degradation of methylene blue dye, under UV exposure was found to increase from 0.27 to 0.36 for 5 mol% doping while very small photo activity has been observed under visible light exposure. Hydrophillicity also shows the same behavior. Optical studies revealed the generation of allowed energy band in the forbidden gap at $0.63 eV below the conduction band. It has been concluded that Mn doping increases photocatalytic activity by scavenging the photogenerated electrons, thereby increasing the life time of charge carriers and increasing the exposed surface area by reducing the crystallite size.
Fruhere Studien weisen auf verschiedene Arten von visuellen Storungen bei der Alzheimer’schen Kra... more Fruhere Studien weisen auf verschiedene Arten von visuellen Storungen bei der Alzheimer’schen Krankheit (ALZ), die sich in Defizienzen in der Kontrastempfindlichkeit, der Stereosehscharfe, der Farben- und Formerkennung und der visuospatialen Orientierung ausdrucken [1–3]. Diese Storungen werden vor allem durch degenerative Veranderungen im visuellen Kortex [1,3] erklart, wahrend die retinocalcarine Funktion relativ gut erhalten bleibt [4]. Nun wurde aber eine alternative Hypothese vorgeschlagen, indem eine Deafferentierung vom primaren visuellen Kortex die Folge einer selektiven Degeneration und eines Verlustes von grosen Ganglienzellen der Retina und von optischen Nervenfasern sein konnte [5, 6]. Als wichtigste Merkmale in der ALZ sind die senile Plaques (SP), mit oder ohne neuritischer Komponente, die neurofibrillaren Knauel (neurofibrillary tangles (NFT)) und neuronaler Verlust [7] zu nennen. Wir haben eine morphologische Studie auf drei Ebenen des visuellen Systems bei der ALZ unternommen: im primaren und sekundaren visuellen Kortex (Areae 17 und 18), im lateralen Nucleus geniculatus (LNG) und im Colliculus superior (CS). Nahere Einzelheiten zur Methode und den Ergebnissen sind anderswo beschrieben [8, 9].
We generated defined neuronal loss in hippocampus of genetically identical mice by pilocarpine in... more We generated defined neuronal loss in hippocampus of genetically identical mice by pilocarpine injections and studied the impact of these seizures on the performance of mice in spatial learning and memory. The numbers of TUNEL-positive degenerating cells paralleled the severity of the seizures. When compared to the numbers found for not-seizured control mice, mild, moderate, and severe seizures produced significant increases in TUNEL-positive neurons in CA1 and CA3 regions by 19, 25, and 63%, respectively. Water maze learning was abolished after the severe seizures. However, spatial learning was normal after mild or moderate seizures. Therefore, there was no linear correlation between the impairment of learning and memory performance with the number of degenerating neurons in hippocampus. Our data suggest that normal spatial learning and memory can be achieved without the full number of hippocampal pyramidal neurons in partially lesioned hippocampus.
potential to spontaneously induce amyloid plaque formation m l~iti-0 under various expenmental co... more potential to spontaneously induce amyloid plaque formation m l~iti-0 under various expenmental conditions. 'The resulta demonstrated that hepariniheparan wlfate GAGS, heparan sulfate-containmg proteoglycans, and related highly sulfated macromolecules effectively induce spontaneous amyloid plaque formation (i.e. maltesecross amyloid-star plaques) in a test tube under the appropriate experimental condmons. Transmission and scanning electron microscopy indicated that such artificially produced amyloid plaqucs were virtually morphologically identical to human amyloid plaques isolated from AD brain. The discovery that highly wlfated GAGS induce spontaneous amyloid plaque formation in rirm further implicates their role m the pathogeneaia of AD leslon development.
The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimer's disease (AD). We h... more The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimer's disease (AD). We have generated transgenic mice expressing BACE and double transgenic mice expressing BACE and the Swedish mutations of APP (SwAPP) in neurons. BACE transgenic mice did not develop bamyloid plaques by age of 14 months, but showed intracellular b-amyloid immunoreactivity that was co-localized with transgenic BACE in neurons. Ab levels were increased and AD-like pathology was accelerated in double transgenic mice expressing both BACE and SwAPP. At two months of age, early signs of extracellular Ab deposition and reactive astrocytes were found in double transgenic, but not in single transgenic mice. Furthermore, at four months, well defined b-amyloid deposits surrounded by activated astrocytes could be detected in the double transgenic mice. We suggest that BACE overexpression is not sufficient to produce b-amyloid plaques, but simultaneous expression of BACE and its substrate (SwAPP) leads to an accelerated amyloid plaque formation.
To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyl... more To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyloid precursor protein (SwAPP) on the vulnerability of central nervous system neurons, we induced epileptic seizures in transgenic mice expressing SwAPP. The transgene expression did not change the seizure threshold, but consistently more neurons degenerated in brains of SwAPP mice as compared with wild-type littermates. The degenerating neurons were stained both by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and by Gallyas silver impregnation. A susceptible population of neurons accumulated intracellular A and immunoreacted with antibodies against activated caspase-3. To demonstrate that increased A levels mediated the increased vulnerability, we infused antibodies against A and found a significant reduction in neuronal loss that was paralleled by decreased brain levels of A. Because the SwAPP mice exhibited no amyloid plaques at the age of these experiments, transgenic overproduction of A in brain rendered neurons susceptible to damage much earlier than the onset of amyloid plaque formation. Our data underscore the possibility that A is toxic, that it increases the vulnerability of neurons to excitotoxic events produced by seizures, and that lowering A by passive immunization can protect neurons from A-related toxicity. Alzheimer's disease (AD) 1 is the most common cause of dementia in the elderly. Both familial and sporadic cases share the deposition in brain of extracellular -amyloid plaques as a common pathological hallmark. -Amyloid is associated with the formation of neurofibrillary tangles, impaired synaptic functions, and the loss of neurons (1-4). -Amyloid deposits are composed of amyloid- peptides (A) that aggregate to form amyloid fibrils (5). Increased generation of the highly amyloidogenic 42-residue form (A 42) is associated with most, if not all, mutations that cause familial AD (6-12). In AD patients
We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the... more We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies.
Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau ge... more Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau gene located on chromosome 17 has been shown to be implicated in the pathogenesis of several FTD families with parkinsonism, the so called FTDP-17 families. The mutations reported so far are located within exons 9 to 13, a region coding for the microtubule-binding sites. They are causing various cytoskeletal disturbances. We are describing here the main clinical and neuropathological features of a Swiss FTD family with members presenting a FTDP-like clinical phenotype. However, if we except two silent polymorphic sites at position 227 and 255 in exon 9, neither a known FTDP-17 mutation nor a novel one was detected in this region of the tau gene. Thus, the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family. A mutation in another gene is still possible. 2000 Academic Press
The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons ... more The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons was studied with the help of an image analysis system (Vidas/Zeiss) in the primary visual area 17 and associative area 18 (Brodmann) of Alzheimer and control brains. In neither of these areas was there a significant difference between Alzheimer and control groups in the mean number of PV, CR, or CB immunoreactive neuronal profiles, counted in a cortical column going from pia to white matter. Significant differences in the mean densities (numbers per square millimeter of cortex) of PV, CR, and CB immunoreactive neuronal profiles were not observed either between groups or areas, but only between superficial, middle, and deep layers within areas 17 and 18. The optical density of the immunoreactive neuropil was also similar in Alzheimer and controls, correlating with the numerical density of immunoreactive profiles in superficial, middle, and deep layers. The frequency distribution of neuronal areas indicated significant differences between PV, CR, and CB immunoreactive neuronal profiles in both areas 17 and 18, with more large PV than CR and CB positive profiles. There were also significantly more small and less large PV and CR immunoreactive neuronal profiles in Alzheimer than in controls. Our data show that, although the brain pathology is moderate to severe, there is no prominent decrease of PV, CR and CB positive neurons in the visual cortex of Alzheimer brains, but only selective changes in neuronal perikarya. 1998 Academic Press
In this study, we quantitatively investigated the expression of β-site amyloid precursor protein ... more In this study, we quantitatively investigated the expression of β-site amyloid precursor protein cleaving enzyme (BACE) in the entorhinohippocampal and frontal cortex of Alzheimer’s disease (AD) and old control subjects. The semiquantitative estimation indicated that the intensity of BACE overall immunoreactivity did not differ significantly between AD and controls, but that a significantly stronger staining was observed in the hippocampal regions CA3–4 compared to other regions in both AD patients and controls. The quantitative estimation confirmed that the number of BACE-positive neuronal profiles was not significantly decreased in AD. However, some degeneration of BACE-positive profiles was attested by the colocalization of neurons expressing BACE and exhibiting neurofibrillary tangles (NFT), as well as by a decrease in the surface area of BACE-positive profiles. In addition, BACE immunocytochemical expression was observed in and around senile plaques (SP), as well as in reactive...
In order to study the patterns of Alzheimer disease (AD)-related pathology in the primary visual ... more In order to study the patterns of Alzheimer disease (AD)-related pathology in the primary visual system of the oldest old, we performed a quantitative analysis of senile plaques (SP), diffuse β amyloid (Aβ) deposit and neurofibrillary tangle (NFT) distribution in primary area 17, and a semi-quantitative analysis in the dorsal lateral geniculate nucleus (LGN), lateral inferior pulvinar (LIP) and superior colliculus (SC) of 21 individuals aged between 93 and 102 years. Among them, 10 cases were considered as non-demented (ND), while 9 presented very mild cognitive impairment (VMCI), and 2 cases had a clinical diagnosis of AD. Silver methenamine and Gallyas staining, Aβ and tau immunostaining revealed the distribution of AD lesions. In primary area 17, most cases, either ND or with VMCI displayed a low to medium number of SP. There was no significant difference in SP and Aβ deposit densities between ND and VMCI groups. On the whole, 0.4–2.4% of the cross-sectional cortical area was cov...
In order to understand relationships between executive and structural deficits in the frontal cor... more In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer's disease, we studied frontal pathological changes in young and old controls compared to cases with sporadic (AD) or familial Alzheimer's disease (FAD). We performed a semi-automatic computer assisted analysis of the distribution of beta-amyloid (Abeta) deposits revealed by Abeta immunostaining as well as of neurofibrillary tangles (NFT) revealed by Gallyas silver staining in Brodman areas 10 (frontal polar), 12 (ventro-infero-median) and 24 (anterior cingular), using tissue samples from 5 FAD, 6 sporadic AD and 10 control brains. We also performed densitometric measurements of glial fibrillary acidic protein, principal compound of intermediate filaments of astrocytes, and of phosphorylated neurofilament H and M epitopes in areas 10 and 24. All regions studied seem almost completely spared in normal old controls, with only the oldest ones exhibiting a weak percentage of beta-amyloid deposit and hardly any NFT. On the contrary, all AD and FAD cases were severely damaged as shown by statistically significant increased percentages of beta-amyloid deposit, as well as by a high number of NFT. FAD cases (all from the same family) had statistically more beta-amyloid and GFAP than sporadic AD cases in both areas 10 and 24 and statistically more NFT only in area 24. The correlation between the percentage of beta-amyloid and the number of NFT was significant only for area 24. Altogether, these data suggest that the frontal cortex can be spared by AD type lesions in normal aging, but is severely damaged in sporadic and still more in familial Alzheimer's disease. The frontal regions appear to be differentially vulnerable, with area 12 having the less amyloid burden, area 24 the less NFT and area 10 having both more amyloid and more NFT. This pattern of damage in frontal regions may represent a strong neuroanatomical support for the deterioration of attention and cognitive capacities as well as for the presence of emotional and behavioral troubles in AD patients.
Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that... more Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases. However, most FTD families have no demonstrable tau mutations. Here we describe the clinical and neuropathological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod score 3.46, θ ⍧ 0 for marker D17S950), but mutations in the tau gene were not found. Clinical symptoms, neuropsychological deficits and neuroimaging findings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and decreased spontaneous speech as the most prominent presenting symptoms. Pathological examination of the Keywords: familial frontotemporal dementia; FTDP-17; ubiquitin-positive inclusions Abbreviations: FTD ϭ frontotemporal dementia; FTDP-17 ϭ frontotemporal dementia and parkinsonism linked to chromosome 17; GFAP ϭ glial fibrillary acidic protein; HMPAO ϭ 99mTc-hexamethyl propyleneamine oxime; IBZM ϭ [ 123 I]iodobenzamide; MC ϭ monoclonal; PC ϭ polyclonal; RT-PCR ϭ reverse transcriptase-polymerase chain reaction; SPECT ϭ single photon emission computed tomography
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Papers by KRISHAN SAINI