Bernd Sommer - Academia.edu (original) (raw)

Papers by Bernd Sommer

Research paper thumbnail of Transgenic Animals in Alzheimer's Disease Research

Reviews in the Neurosciences, 1999

Alzheimer's disease (AD) is a neurodegenerative disorder of the brain accounting for abou... more Alzheimer's disease (AD) is a neurodegenerative disorder of the brain accounting for about 50-70% of the typical late onset cases of dementia. The pathological and diagnostic hallmarks of the disease are principally the presence of extracellular deposits called neuritic amyloid plaques and the intracellular aggregation of neurofibrillary tangles. In addition selective neuronal cell loss accompanied by cerebrovascular amyloidosis is detectable. In the case of familial AD, defects in at least three different genes (APP, PS1, PS2) leading to indistinguishable pathology are now well defined. There is as yet no real treatment for AD. Therefore the availability of an easily manipulable animal model is crucial for the development of new drugs, which could slow down or, even better, stop the progression of the disease. The development and originality of such experimental models that could greatly facilitate the investigation of the aetiology and pathogenesis of AD are described and discussed in this review. They are based mainly on the attempt to reproduce the neurofibrillary tangles or the amyloid deposits and plaque formation.

Research paper thumbnail of Transgenic Approaches to Model Alzheimer's Disease

Reviews in the Neurosciences, 2000

Two transgenic mouse lines were generated which express human APP751 containing familial Alzheime... more Two transgenic mouse lines were generated which express human APP751 containing familial Alzheimer's disease (AD) mutations in brain neurons. These mice develop pathological features reminiscent of AD. The degree of pathology depends on both expression levels and specific mutations. In mice with more advanced pathology (APP 23), typical plaques appear at six months which increase with age and are Congo Red positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. A quantitative analysis of degenerative changes by state-of-the-art unbiased stereological methods revealed a significant reduction in neuronal cell bodies of the CA1 field of the hippocampus when compared to controls. This reduction is directly related to plaque load. When subjected to analysis in the Morris water maze, 18 month old APP 23 mice show a significant increase in platform finding latency throughout the entire trial when compared to non-transgenic littermates.

Research paper thumbnail of Histochemical localization of A� peptide in APP 23 mouse brain

Research paper thumbnail of Binding of nuclear proteins to promoter elements of the mouse alpha A-crystallin gene

Journal of Biological Chemistry

We have investigated the binding of nuclear proteins from the embryonic chicken lens to synthetic... more We have investigated the binding of nuclear proteins from the embryonic chicken lens to synthetic oligonucleotides derived from sequence -111/-55 of the murine alpha A-crystallin gene. These sequences were shown previously to consist of a distal (-111/-88) and a proximal (-88/-60) region which are required for expression of this gene (Chepelinsky, A. B., Sommer, B., and Piatigorsky, J. (1987) Mol. Cell. Biol. 7, 1807-1814). Here we use gel retardation and methylation interference experiments to provide evidence for selective binding of different nuclear proteins to oligonucleotides containing sequences -111/-84, -83/-55, and -111/-55. Similar (although not necessarily identical) proteins were found in nuclear extracts of chicken erythrocytes and HeLa cells. Despite this fact, the alpha A-crystallin promoter (-111/+46) did not function in transfected HeLa cells; moreover, deletion experiments showed that only the TATA box is required for activity of this promoter in a HeLa whole cell extract, the distal (-111/84) and proximal (-83/-55) elements having no positive effect on transcription in the HeLa cell extract. These experiments support the idea that the same or related nuclear proteins found in many tissues are necessary but not sufficient for expression of the murine alpha A-crystallin gene.

Research paper thumbnail of Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease

Nature Neuroscience

Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fib... more Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Aβ is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Aβ to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Aβ bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Aβ neurotoxicity suggested that Aβ neurotoxicity involves APP. Thus Aβ toxicity may be mediated by the interaction of fibrillar Aβ with neuronal membrane proteins, notably APP. An Aβ-APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.

Research paper thumbnail of A glutamate receptor channel with high affinity for domoate and kainate

The EMBO Journal

The non-NMDA family of glutamate receptors comprises a growing number of structurally related sub... more The non-NMDA family of glutamate receptors comprises a growing number of structurally related subunits (GluR-A to-D or-1 to 4; GluR-5,-6; KA-1). GluR-A to-D appear to constitute the major AMPA receptor subtypes but the functional and pharmacological characteristics of the other subunits are unresolved. Using a mammalian expression system we demonstrate here that homomeric GIuR-5 receptors exhibit properties of a high affinity domoate (KD-2 nM) and kainate (KD-70 nM) binding site. For these receptors, the rank order of ligands competing with [ H]kainate binding was domoate >> quisqualate = glutamate >> AMPA = CNQX. The respective receptor channels were gated in decreasing order of sensitivity by domoate, kainate, glutamate and AMPA. In contrast to recombinantly expressed GluR-A to-D channels, currents elicited at GluR-5 receptor desensitize channels to all agonists. This property is characteristic of currents in peripheral neurons on sensory ganglia. These fmdings suggest the existence of at least two distinct types of non-NMDA receptor channels, both gated by AMPA and kainate, but differing in pharmacology and current properties.

Research paper thumbnail of Cerebral Amyloid Induces Aberrant Axonal Sprouting and Ectopic Terminal Formation in Amyloid Precursor Protein Transgenic Mice

The Journal of Neuroscience

A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the b... more A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.

Research paper thumbnail of Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis

The Journal of Neuroscience

This work was supported by grants from the Swiss National Science Foundation and the VerUm Founda... more This work was supported by grants from the Swiss National Science Foundation and the VerUm Foundation (Munich, Germany). We thank J. Massoulie for providing antibodies, P. Mouton for helpful comments regarding stereological procedures, D. Hunziker for technical assistance, and T. Schürch and H. Zysset for assistance in photography.

Research paper thumbnail of The dopamine D2 receptor: two molecular forms generated by alternative splicing

The EMBO Journal

Cloned human dopamine D2 receptor cDNA was isolated from a pituitary cDNA library and found to en... more Cloned human dopamine D2 receptor cDNA was isolated from a pituitary cDNA library and found to encode an additional 29 amino acid residues in the predicted intracellular domain between transmembrane regions 5 and 6 relative to a previously described rat brain D2 receptor. Results from polymerase chain reactions as well as in situ hybridization revealed that mRNA encoding both receptor forms is present in pituitary and brain of both rat and man. The larger form was predominant in these tissues and, as shown in the rat, expressed by dopaminergic and dopaminoceptive neurons. Analysis of the human gene showed that the additional peptide sequence is encoded by a separate exon. Hence, the two receptor forms are generated by differential splicing possibly to permit coupling to different G proteins. Both receptors expressed in cultured mammalian cells bind [3H]spiperone with high affinity and inhibit adenylyl cyclase, as expected of the D2 receptor subtype.

Research paper thumbnail of Neuronal Localization of Presenilin-1 and Association with Amyloid Plaques and Neurofibrillary Tangles in Alzheimer’s Disease

The Journal of Neuroscience

Mutations in the presenilin-1 (PS1) gene is a cause of earlyonset familial Alzheimer's disease (A... more Mutations in the presenilin-1 (PS1) gene is a cause of earlyonset familial Alzheimer's disease (AD). Endogenous PS1 is associated with the endoplasmic reticulum in the cell body of undifferentiated SH-SY5Y neuroblastoma cells. At early stages of neuronal differentiation in rat hippocampal culture, PS1 appears in all neuritic processes and in growth cones. In mature differentiated neurons, PS1 is concentrated in the somatodendritic compartment but is also present at lower levels in axons. A similar localization of PS1 is observed in vivo in neurons of the adult human cerebral cortex. In sporadic AD, PS1 appears in the dystrophic neurites of mature amyloid plaques and colocalizes with a subset of intraneuronal neurofibrillary tangles (NFTs). About 30% of hippocampal NFTs are labeled with a highly specific antibody to the PS1 C-terminal loop domain but not with an antibody to the PS1 N terminus. This observation is consistent with a potential association of the PS1 C-terminal fragment with NFTs, because PS1 is constitutively cleaved to N-and C-terminal fragments in neurons. These results suggest that PS1 is highly expressed and broadly distributed during early stages of neuronal differentiation, consistent with a role for PS1 in neuronal differentiation. Furthermore, the co-localization of PS1 with NFTs and plaque dystrophic neurites implicates a role for PS1 in the diverse pathological manifestations of AD.

Research paper thumbnail of Neuropathology in Mice Expressing Human α-Synuclein

The Journal of Neuroscience

Research paper thumbnail of Neuron loss in APP transgenic mice

Nature

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large pr... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large proportion of the elderly population. Amyloid plaques, which are a neuro-pathological characteristic of AD, have been reproduced in transgenic mice by the overexpression of mutant forms of ...

Research paper thumbnail of Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

Proceedings of the National Academy of Sciences

Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmar... more Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer’s disease pathology, namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid β (Aβ) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer’s disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of Aβ in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways r...

Research paper thumbnail of Tau hyperphosphorylation in transgenic mice expressing the APP double mutation

Research paper thumbnail of Dystriphic neurites in plaque-like A$beta;deposits in mice double transgenic for the APP 670/671 mutation and the human four-repeat tau protein

Research paper thumbnail of The Murine GABA A Receptor d-Subunit Gene: Structure and Assignment to Human Chromosome 1

Research paper thumbnail of Transgenic animal model for alzheimer disease

Research paper thumbnail of A�-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice

Research paper thumbnail of Flibanserin-Stimulated Partner Grooming Reflects Brain Metabolism Changes in Female Marmosets

The journal of sexual medicine, 2015

Female sexual interest and arousal disorder is personally distressing for women. To better unders... more Female sexual interest and arousal disorder is personally distressing for women. To better understand the mechanism of the candidate therapeutic, flibanserin, we determined its effects on an index of brain glucose metabolism. We hypothesized that chronic treatment with flibanserin would alter metabolism in brain regions associated with serotonergic function and female sexual behavior. In a crossover design, eight adult female common marmosets (Calithrix jacchus) received daily flibanserin or vehicle. After 7-12 weeks of treatment, the glucose metabolism radiotracer [(18) F]fluorodeoxyglucose (FDG) was administered to each female immediately prior to 30 minutes of interaction with her male pairmate, after which females were anesthetized and imaged by positron emission tomography. Whole-brain normalized images were analyzed with anatomically defined regions of interest. Whole-brain voxelwise mapping was used to explore treatment effects. Correlations were examined between alterations ...

Research paper thumbnail of Nogo Receptor Homologues and Their Use

Research paper thumbnail of Transgenic Animals in Alzheimer's Disease Research

Reviews in the Neurosciences, 1999

Alzheimer's disease (AD) is a neurodegenerative disorder of the brain accounting for abou... more Alzheimer's disease (AD) is a neurodegenerative disorder of the brain accounting for about 50-70% of the typical late onset cases of dementia. The pathological and diagnostic hallmarks of the disease are principally the presence of extracellular deposits called neuritic amyloid plaques and the intracellular aggregation of neurofibrillary tangles. In addition selective neuronal cell loss accompanied by cerebrovascular amyloidosis is detectable. In the case of familial AD, defects in at least three different genes (APP, PS1, PS2) leading to indistinguishable pathology are now well defined. There is as yet no real treatment for AD. Therefore the availability of an easily manipulable animal model is crucial for the development of new drugs, which could slow down or, even better, stop the progression of the disease. The development and originality of such experimental models that could greatly facilitate the investigation of the aetiology and pathogenesis of AD are described and discussed in this review. They are based mainly on the attempt to reproduce the neurofibrillary tangles or the amyloid deposits and plaque formation.

Research paper thumbnail of Transgenic Approaches to Model Alzheimer's Disease

Reviews in the Neurosciences, 2000

Two transgenic mouse lines were generated which express human APP751 containing familial Alzheime... more Two transgenic mouse lines were generated which express human APP751 containing familial Alzheimer's disease (AD) mutations in brain neurons. These mice develop pathological features reminiscent of AD. The degree of pathology depends on both expression levels and specific mutations. In mice with more advanced pathology (APP 23), typical plaques appear at six months which increase with age and are Congo Red positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. A quantitative analysis of degenerative changes by state-of-the-art unbiased stereological methods revealed a significant reduction in neuronal cell bodies of the CA1 field of the hippocampus when compared to controls. This reduction is directly related to plaque load. When subjected to analysis in the Morris water maze, 18 month old APP 23 mice show a significant increase in platform finding latency throughout the entire trial when compared to non-transgenic littermates.

Research paper thumbnail of Histochemical localization of A� peptide in APP 23 mouse brain

Research paper thumbnail of Binding of nuclear proteins to promoter elements of the mouse alpha A-crystallin gene

Journal of Biological Chemistry

We have investigated the binding of nuclear proteins from the embryonic chicken lens to synthetic... more We have investigated the binding of nuclear proteins from the embryonic chicken lens to synthetic oligonucleotides derived from sequence -111/-55 of the murine alpha A-crystallin gene. These sequences were shown previously to consist of a distal (-111/-88) and a proximal (-88/-60) region which are required for expression of this gene (Chepelinsky, A. B., Sommer, B., and Piatigorsky, J. (1987) Mol. Cell. Biol. 7, 1807-1814). Here we use gel retardation and methylation interference experiments to provide evidence for selective binding of different nuclear proteins to oligonucleotides containing sequences -111/-84, -83/-55, and -111/-55. Similar (although not necessarily identical) proteins were found in nuclear extracts of chicken erythrocytes and HeLa cells. Despite this fact, the alpha A-crystallin promoter (-111/+46) did not function in transfected HeLa cells; moreover, deletion experiments showed that only the TATA box is required for activity of this promoter in a HeLa whole cell extract, the distal (-111/84) and proximal (-83/-55) elements having no positive effect on transcription in the HeLa cell extract. These experiments support the idea that the same or related nuclear proteins found in many tissues are necessary but not sufficient for expression of the murine alpha A-crystallin gene.

Research paper thumbnail of Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease

Nature Neuroscience

Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fib... more Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Aβ is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Aβ to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Aβ bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Aβ neurotoxicity suggested that Aβ neurotoxicity involves APP. Thus Aβ toxicity may be mediated by the interaction of fibrillar Aβ with neuronal membrane proteins, notably APP. An Aβ-APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.

Research paper thumbnail of A glutamate receptor channel with high affinity for domoate and kainate

The EMBO Journal

The non-NMDA family of glutamate receptors comprises a growing number of structurally related sub... more The non-NMDA family of glutamate receptors comprises a growing number of structurally related subunits (GluR-A to-D or-1 to 4; GluR-5,-6; KA-1). GluR-A to-D appear to constitute the major AMPA receptor subtypes but the functional and pharmacological characteristics of the other subunits are unresolved. Using a mammalian expression system we demonstrate here that homomeric GIuR-5 receptors exhibit properties of a high affinity domoate (KD-2 nM) and kainate (KD-70 nM) binding site. For these receptors, the rank order of ligands competing with [ H]kainate binding was domoate >> quisqualate = glutamate >> AMPA = CNQX. The respective receptor channels were gated in decreasing order of sensitivity by domoate, kainate, glutamate and AMPA. In contrast to recombinantly expressed GluR-A to-D channels, currents elicited at GluR-5 receptor desensitize channels to all agonists. This property is characteristic of currents in peripheral neurons on sensory ganglia. These fmdings suggest the existence of at least two distinct types of non-NMDA receptor channels, both gated by AMPA and kainate, but differing in pharmacology and current properties.

Research paper thumbnail of Cerebral Amyloid Induces Aberrant Axonal Sprouting and Ectopic Terminal Formation in Amyloid Precursor Protein Transgenic Mice

The Journal of Neuroscience

A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the b... more A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.

Research paper thumbnail of Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis

The Journal of Neuroscience

This work was supported by grants from the Swiss National Science Foundation and the VerUm Founda... more This work was supported by grants from the Swiss National Science Foundation and the VerUm Foundation (Munich, Germany). We thank J. Massoulie for providing antibodies, P. Mouton for helpful comments regarding stereological procedures, D. Hunziker for technical assistance, and T. Schürch and H. Zysset for assistance in photography.

Research paper thumbnail of The dopamine D2 receptor: two molecular forms generated by alternative splicing

The EMBO Journal

Cloned human dopamine D2 receptor cDNA was isolated from a pituitary cDNA library and found to en... more Cloned human dopamine D2 receptor cDNA was isolated from a pituitary cDNA library and found to encode an additional 29 amino acid residues in the predicted intracellular domain between transmembrane regions 5 and 6 relative to a previously described rat brain D2 receptor. Results from polymerase chain reactions as well as in situ hybridization revealed that mRNA encoding both receptor forms is present in pituitary and brain of both rat and man. The larger form was predominant in these tissues and, as shown in the rat, expressed by dopaminergic and dopaminoceptive neurons. Analysis of the human gene showed that the additional peptide sequence is encoded by a separate exon. Hence, the two receptor forms are generated by differential splicing possibly to permit coupling to different G proteins. Both receptors expressed in cultured mammalian cells bind [3H]spiperone with high affinity and inhibit adenylyl cyclase, as expected of the D2 receptor subtype.

Research paper thumbnail of Neuronal Localization of Presenilin-1 and Association with Amyloid Plaques and Neurofibrillary Tangles in Alzheimer’s Disease

The Journal of Neuroscience

Mutations in the presenilin-1 (PS1) gene is a cause of earlyonset familial Alzheimer's disease (A... more Mutations in the presenilin-1 (PS1) gene is a cause of earlyonset familial Alzheimer's disease (AD). Endogenous PS1 is associated with the endoplasmic reticulum in the cell body of undifferentiated SH-SY5Y neuroblastoma cells. At early stages of neuronal differentiation in rat hippocampal culture, PS1 appears in all neuritic processes and in growth cones. In mature differentiated neurons, PS1 is concentrated in the somatodendritic compartment but is also present at lower levels in axons. A similar localization of PS1 is observed in vivo in neurons of the adult human cerebral cortex. In sporadic AD, PS1 appears in the dystrophic neurites of mature amyloid plaques and colocalizes with a subset of intraneuronal neurofibrillary tangles (NFTs). About 30% of hippocampal NFTs are labeled with a highly specific antibody to the PS1 C-terminal loop domain but not with an antibody to the PS1 N terminus. This observation is consistent with a potential association of the PS1 C-terminal fragment with NFTs, because PS1 is constitutively cleaved to N-and C-terminal fragments in neurons. These results suggest that PS1 is highly expressed and broadly distributed during early stages of neuronal differentiation, consistent with a role for PS1 in neuronal differentiation. Furthermore, the co-localization of PS1 with NFTs and plaque dystrophic neurites implicates a role for PS1 in the diverse pathological manifestations of AD.

Research paper thumbnail of Neuropathology in Mice Expressing Human α-Synuclein

The Journal of Neuroscience

Research paper thumbnail of Neuron loss in APP transgenic mice

Nature

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large pr... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large proportion of the elderly population. Amyloid plaques, which are a neuro-pathological characteristic of AD, have been reproduced in transgenic mice by the overexpression of mutant forms of ...

Research paper thumbnail of Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

Proceedings of the National Academy of Sciences

Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmar... more Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer’s disease pathology, namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid β (Aβ) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer’s disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of Aβ in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways r...

Research paper thumbnail of Tau hyperphosphorylation in transgenic mice expressing the APP double mutation

Research paper thumbnail of Dystriphic neurites in plaque-like A$beta;deposits in mice double transgenic for the APP 670/671 mutation and the human four-repeat tau protein

Research paper thumbnail of The Murine GABA A Receptor d-Subunit Gene: Structure and Assignment to Human Chromosome 1

Research paper thumbnail of Transgenic animal model for alzheimer disease

Research paper thumbnail of A�-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice

Research paper thumbnail of Flibanserin-Stimulated Partner Grooming Reflects Brain Metabolism Changes in Female Marmosets

The journal of sexual medicine, 2015

Female sexual interest and arousal disorder is personally distressing for women. To better unders... more Female sexual interest and arousal disorder is personally distressing for women. To better understand the mechanism of the candidate therapeutic, flibanserin, we determined its effects on an index of brain glucose metabolism. We hypothesized that chronic treatment with flibanserin would alter metabolism in brain regions associated with serotonergic function and female sexual behavior. In a crossover design, eight adult female common marmosets (Calithrix jacchus) received daily flibanserin or vehicle. After 7-12 weeks of treatment, the glucose metabolism radiotracer [(18) F]fluorodeoxyglucose (FDG) was administered to each female immediately prior to 30 minutes of interaction with her male pairmate, after which females were anesthetized and imaged by positron emission tomography. Whole-brain normalized images were analyzed with anatomically defined regions of interest. Whole-brain voxelwise mapping was used to explore treatment effects. Correlations were examined between alterations ...

Research paper thumbnail of Nogo Receptor Homologues and Their Use