Jeffrey Keller | University of Cincinnati College of Medicine (original) (raw)

Papers by Jeffrey Keller

Research paper thumbnail of Flow and thermal structures in a transitional boundary layer

Experimental Thermal and Fluid Science, 1996

Research paper thumbnail of Paratrigeminal, Paraclival, Precavernous, or All of the Above? A Circumferential Anatomical Study of the C3-C4 Transitional Segment of the Internal Carotid Artery

Operative neurosurgery (Hagerstown, Md.), Jan 21, 2017

Although the term paraclival carotid pervades recent skull base literature, no clear consensus ex... more Although the term paraclival carotid pervades recent skull base literature, no clear consensus exists regarding boundaries or anatomical segments. To reconcile various internal carotid artery (ICA) nomenclatures for transcranial and endoscopic-endonasal perspectives, we reexamined the transition between lacerum (C3) and cavernous (C4) segments using a C1-C7 segments schema. In this cadaveric study, we obtained a 360°-circumferential view integrating histological, microsurgical, endoscopic, and neuroradiological analyses of this C3-C4 region and identified a distinct transitional segment. In 13 adult, silicone-injected, formalin-fixed cadaveric heads (26 sides), transcranial-extradural-subtemporal and endoscopic-endonasal CT-guided dissections were performed. A quadrilateral area was noted medial to Meckel's cave between cranial nerve VI, anterolateral and posterolateral borders of the lateral-paratrigeminal aspect of the precavernous ICA, and posterior longitudinal ligament. End...

Research paper thumbnail of Comparison of rat liver and brain proteasomes for oxidative stress-induced inactivation: Influence of ageing and dietary restriction

Http Dx Doi Org 10 1080 10715760802534812, 2009

Research paper thumbnail of Age-related Alterations of Apolipoprotein E and Interleukin-1 � in the Aging Brain

Biogerontology, 2006

With normal aging, the brain undergoes several alterations including reduced neuronal functioning... more With normal aging, the brain undergoes several alterations including reduced neuronal functioning and alterations in glia homeostasis. An increase in inflammatory signaling has also been reported in some studies of the aging brain, with inflammation potentially mediating age-related changes in the brain. Apolipoprotein E (ApoE) is produced in the brain and has been shown to possess anti-inflammatory properties in a variety of paradigms. In the present study, we correlated age-related alterations in ApoE expression with age-related changes in the cytokine interleukin-1 beta (IL-1beta), in the brain of rats of increasing age. No significant alteration in ApoE mRNA was found in any region examined. A significant increase in IL-1beta mRNA with age was observed only in the cortex. Neither ApoE nor IL-1beta protein expression was significantly altered with age in the brain. A significant linear correlation between ApoE and IL-1beta mRNA was found in the cortex but not in the striatum or hippocampus. No correlation was found between ApoE and IL-1beta protein in any region examined. Taken together, these studies demonstrate that ApoE expression is not altered during normal brain aging, but suggest that there may be a relationship between ApoE and IL-1beta transcription in the cerebral cortex.

Research paper thumbnail of Modulation of apolipoprotein E and interleukin-1� in the aging liver

Exp Gerontol, 2005

With aging there is a decline in liver function that includes reductions in hepatic blood flow, m... more With aging there is a decline in liver function that includes reductions in hepatic blood flow, metabolite clearance, and impaired tissue repair following injury. An increase in inflammatory signaling is often observed during aging, with inflammation potentially mediating age-related changes in the liver. Apolipoprotein E (ApoE) is primarily produced by the liver and has been shown to possess anti-inflammatory properties in a variety of paradigms and experimental settings. In the present study, we correlated age-related alterations in ApoE expression with age-related changes in the cytokine interleukin-1 beta (IL-1β), in the liver of rats of increasing age. A significant increase in ApoE mRNA, and a significant decrease in IL-1β mRNA, was seen with increasing age. At the protein level, ApoE expression increased with aging, although IL-1β expression remained constant. No correlation was found between ApoE and IL-1β expression at the mRNA or protein level. Taken together, these studies demonstrate that ApoE expression is altered during normal aging, and indicates that there is no correlation between ApoE and IL-1β expression in the aging liver.

Research paper thumbnail of Amyloid �-Peptide Effects on Synaptosomes from Apolipoprotein E-Deficient Mice

Research paper thumbnail of Oxidized Low-Density Lipoprotein Induces Neuronal Death: Implications for Calcium, Reactive Oxygen Species, and Caspases

Research paper thumbnail of Lessons in the Study of Alzheimer�s Disease: A Tribute to Dr. William R. Markesbery

Neuromolecular Medicine, Mar 1, 2011

Research paper thumbnail of Effect of soil depth on phytoremediation efficiency for petroleum contaminants

J Environ Sci Health a, 2007

Biodegradation of organic contaminants in soil may be enhanced by the presence of vegetation. Eva... more Biodegradation of organic contaminants in soil may be enhanced by the presence of vegetation. Evaluating the effect of soil depth on phytoremediation efficiency may provide researchers and regulators with a clearer understanding of contaminant clean-up. A column study with polycyclic aromatic hydrocarbons (PAHs) and diesel-contaminated soil was conducted over a 147-day period of switchgrass (Panicum virgatum) growth. Analysis of the contaminants and plant biomass was conducted along with microbial enumeration at three soil depths in 49-day intervals. Remediation proceeded rapidly near the surface of the soil (0-20 cm) for both vegetated and unvegetated columns, but the effect of vegetation relative to an unvegetated control only was significant in the lower soil depths. Contaminant dissipation in the 20-40 and 40-60 cm layers was not significantly different between vegetated and unvegetated soil.

Research paper thumbnail of Analysis of oxidative stress in mouse model of cerebral amyloid angiopathy (CAA)

The Faseb Journal, Apr 1, 2009

Research paper thumbnail of Traumatic Brain Injury Alters Synaptic Homeostasis: Implications for Impaired Mitochondrial and Transport Function

Journal of Neurotrauma, Nov 1, 1998

This study utilized a unilateral controlled cortical impact model of traumatic brain injury to as... more This study utilized a unilateral controlled cortical impact model of traumatic brain injury to assess disruptions of synaptic homeostasis following trauma. Adult rats were subjected to a moderate (2 mm) cortical deformation and synaptosomes were prepared from the entire ipsilateral (injured) hemisphere or dissected into different regions (hippocampus, injured cortical area including penumbra, residual hemisphere) at various times postinjury (10 and 30 min, and 1, 6, and 24 h). Synaptosomes from the corresponding regions of the contralateral hemisphere were used as controls to assess alterations in synaptic ATP levels, lipid peroxidation, and glutamate and glucose transport. The results demonstrate significant time-dependent alterations in synaptic homeostasis, which included an immediate reduction in ATP levels, coupled with a significant increase in lipid peroxidation within 30 min postinjury. Lipid peroxidation demonstrated a biphasic response with elevations observed 24 h postinjury, a time at which decreases in glutamate and glucose transport occurred. These results suggest that disruption of synaptic homeostasis is an extremely early event following trauma that should be considered when designing pharmacological interventions.

Research paper thumbnail of Integrin �2 Mediates Selective Metastasis to the Liver

Cancer Res, 2009

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad a... more Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

Research paper thumbnail of Lysophosphatidic Acid Induces Necrosis and Apoptosis in Hippocampal Neurons

Journal of Neurochemistry, 1998

A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA)... more A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA) in the CNS. This study identifies and characterizes the induction of neuronal death by LPA. Treatment of cultured hippocampal neurons from embryonic rat brains with 50 microM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10 microM led to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 microM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 microM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserine, and protection against chromatin condensation, TUNEL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1beta converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 microM LPA. LPA (1 microM) also induced a decrease in mitochondrial membrane potential. Moreover, pretreatment of neurons with cyclosporin A protected against the LPA-induced decrease in mitochondrial membrane potential and neuronal apoptosis. Thus, LPA, at pathophysiological levels, can induce neuronal apoptosis and could thereby participate in neurodegenerative disorders.

Research paper thumbnail of Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain

The Journal of Neuroscience the Official Journal of the Society For Neuroscience, Sep 10, 2003

Research paper thumbnail of Lysophosphatidic Acid Decreases Glutamate and Glucose Uptake by Astrocytes

Research paper thumbnail of Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice

The Journal of Nutritional Biochemistry, 2015

Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies ... more Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies have suggested that EVOO has several health promoting effects that could protect from and decrease the risk of Alzheimer's disease (AD). In this study, we investigated the effect of consumption of EVOO-enriched diet on amyloid- and tau-related pathological alterations that are associated with the progression of AD and cerebral amyloid angiopathy (CAA) in TgSwDI mice. Feeding mice with EVOO-enriched diet for 6months, beginning at an age before amyloid-β (Aβ) accumulation starts, has significantly reduced total Aβ and tau brain levels with a significant improvement in mouse cognitive behavior. This reduction in brain Aβ was explained by the enhanced Aβ clearance pathways and reduced brain production of Aβ via modulation of amyloid-β precursor protein processing. On the other hand, although feeding mice with EVOO-enriched diet for 3months, beginning at an age after Aβ accumulation starts, showed improved clearance across the blood-brain barrier and significant reduction in Aβ levels, it did not affect tau levels or improve cognitive functions of TgSwDI mouse. Collectively, results of this study suggest that the long-term consumption of EVOO-containing diet starting at early age provides a protective effect against AD and its related disorder CAA.

Research paper thumbnail of Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1999

Apolipoprotein E (apoE)-related synthetic peptides, the 22 kDa N-terminal thrombin-cleavage fragm... more Apolipoprotein E (apoE)-related synthetic peptides, the 22 kDa N-terminal thrombin-cleavage fragment of apoE (truncated apoE), and full-length apoE have all been shown to exhibit neurotoxic activity under certain culture conditions. In the present study, protease inhibitors reduced the neurotoxicity and proteolysis of full-length apoE but did not block the toxicity of truncated apoE or a synthetic apoE peptide, suggesting that fragments of apoE may account for its toxicity. Additional experiments demonstrated that both truncated apoE and the apoE peptide elicit an increase in intracellular calcium levels and subsequent death of embryonic rat hippocampal neurons in culture. Similar effects on calcium were found when the apoE peptide was applied to chick sympathetic neurons. The rise in intracellular calcium and the hippocampal cell death caused by the apoE peptide were significantly reduced by receptor-associated protein, removal of extracellular calcium, or administration of the spe...

Research paper thumbnail of Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998

Many cases of autosomal dominant early onset Alzheimer's disease (AD) result from mutations i... more Many cases of autosomal dominant early onset Alzheimer's disease (AD) result from mutations in the gene encoding presenilin-1 (PS-1). PS-1 is an integral membrane protein expressed ubiquitously in neurons throughout the brain in which it is located primarily in endoplasmic reticulum (ER). Although the pathogenic mechanism of PS-1 mutations is unknown, recent findings suggest that PS mutations render neurons vulnerable to apoptosis. Because increasing evidence indicates that mitochondrial alterations contribute to neuronal death in AD, we tested the hypothesis that PS-1 mutations sensitize neurons to mitochondrial failure. PC12 cell lines expressing a PS-1 mutation (L286V) exhibited increased sensitivity to apoptosis induced by 3-nitropropionic acid (3-NP) and malonate, inhibitors of succinate dehydrogenase, compared with control cell lines and lines overexpressing wild-type PS-1. The apoptosis-enhancing action of mutant PS-1 was prevented by antioxidants (propyl gallate and glut...

Research paper thumbnail of Interplay between protein synthesis and degradation in the CNS: physiological and pathological implications

Trends in neurosciences, 2007

Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiologic... more Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiological abnormalities and pathologies in the CNS. This could be because reduced protein turnover leads to bulk intracellular protein accumulation. However, conditions associated with compromised UPS function are also associated with impairments in protein synthesis, and impairment of UPS function is sufficient to inhibit protein synthesis. These data suggest that the toxicity of UPS inhibition need not depend on gross intracellular protein accumulation, and indicate the potential for crosstalk between the UPS and protein-synthesis pathways. In this review, we discuss evidence for interplay between the UPS and protein-synthesis machinery, and outline the implications of this crosstalk for physiological and pathological processes in the CNS.

Research paper thumbnail of Diet and age interactions with regards to cholesterol regulation and brain pathogenesis

Current gerontology and geriatrics research, 2010

Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its num... more Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolem...

Research paper thumbnail of Flow and thermal structures in a transitional boundary layer

Experimental Thermal and Fluid Science, 1996

Research paper thumbnail of Paratrigeminal, Paraclival, Precavernous, or All of the Above? A Circumferential Anatomical Study of the C3-C4 Transitional Segment of the Internal Carotid Artery

Operative neurosurgery (Hagerstown, Md.), Jan 21, 2017

Although the term paraclival carotid pervades recent skull base literature, no clear consensus ex... more Although the term paraclival carotid pervades recent skull base literature, no clear consensus exists regarding boundaries or anatomical segments. To reconcile various internal carotid artery (ICA) nomenclatures for transcranial and endoscopic-endonasal perspectives, we reexamined the transition between lacerum (C3) and cavernous (C4) segments using a C1-C7 segments schema. In this cadaveric study, we obtained a 360°-circumferential view integrating histological, microsurgical, endoscopic, and neuroradiological analyses of this C3-C4 region and identified a distinct transitional segment. In 13 adult, silicone-injected, formalin-fixed cadaveric heads (26 sides), transcranial-extradural-subtemporal and endoscopic-endonasal CT-guided dissections were performed. A quadrilateral area was noted medial to Meckel's cave between cranial nerve VI, anterolateral and posterolateral borders of the lateral-paratrigeminal aspect of the precavernous ICA, and posterior longitudinal ligament. End...

Research paper thumbnail of Comparison of rat liver and brain proteasomes for oxidative stress-induced inactivation: Influence of ageing and dietary restriction

Http Dx Doi Org 10 1080 10715760802534812, 2009

Research paper thumbnail of Age-related Alterations of Apolipoprotein E and Interleukin-1 � in the Aging Brain

Biogerontology, 2006

With normal aging, the brain undergoes several alterations including reduced neuronal functioning... more With normal aging, the brain undergoes several alterations including reduced neuronal functioning and alterations in glia homeostasis. An increase in inflammatory signaling has also been reported in some studies of the aging brain, with inflammation potentially mediating age-related changes in the brain. Apolipoprotein E (ApoE) is produced in the brain and has been shown to possess anti-inflammatory properties in a variety of paradigms. In the present study, we correlated age-related alterations in ApoE expression with age-related changes in the cytokine interleukin-1 beta (IL-1beta), in the brain of rats of increasing age. No significant alteration in ApoE mRNA was found in any region examined. A significant increase in IL-1beta mRNA with age was observed only in the cortex. Neither ApoE nor IL-1beta protein expression was significantly altered with age in the brain. A significant linear correlation between ApoE and IL-1beta mRNA was found in the cortex but not in the striatum or hippocampus. No correlation was found between ApoE and IL-1beta protein in any region examined. Taken together, these studies demonstrate that ApoE expression is not altered during normal brain aging, but suggest that there may be a relationship between ApoE and IL-1beta transcription in the cerebral cortex.

Research paper thumbnail of Modulation of apolipoprotein E and interleukin-1� in the aging liver

Exp Gerontol, 2005

With aging there is a decline in liver function that includes reductions in hepatic blood flow, m... more With aging there is a decline in liver function that includes reductions in hepatic blood flow, metabolite clearance, and impaired tissue repair following injury. An increase in inflammatory signaling is often observed during aging, with inflammation potentially mediating age-related changes in the liver. Apolipoprotein E (ApoE) is primarily produced by the liver and has been shown to possess anti-inflammatory properties in a variety of paradigms and experimental settings. In the present study, we correlated age-related alterations in ApoE expression with age-related changes in the cytokine interleukin-1 beta (IL-1β), in the liver of rats of increasing age. A significant increase in ApoE mRNA, and a significant decrease in IL-1β mRNA, was seen with increasing age. At the protein level, ApoE expression increased with aging, although IL-1β expression remained constant. No correlation was found between ApoE and IL-1β expression at the mRNA or protein level. Taken together, these studies demonstrate that ApoE expression is altered during normal aging, and indicates that there is no correlation between ApoE and IL-1β expression in the aging liver.

Research paper thumbnail of Amyloid �-Peptide Effects on Synaptosomes from Apolipoprotein E-Deficient Mice

Research paper thumbnail of Oxidized Low-Density Lipoprotein Induces Neuronal Death: Implications for Calcium, Reactive Oxygen Species, and Caspases

Research paper thumbnail of Lessons in the Study of Alzheimer�s Disease: A Tribute to Dr. William R. Markesbery

Neuromolecular Medicine, Mar 1, 2011

Research paper thumbnail of Effect of soil depth on phytoremediation efficiency for petroleum contaminants

J Environ Sci Health a, 2007

Biodegradation of organic contaminants in soil may be enhanced by the presence of vegetation. Eva... more Biodegradation of organic contaminants in soil may be enhanced by the presence of vegetation. Evaluating the effect of soil depth on phytoremediation efficiency may provide researchers and regulators with a clearer understanding of contaminant clean-up. A column study with polycyclic aromatic hydrocarbons (PAHs) and diesel-contaminated soil was conducted over a 147-day period of switchgrass (Panicum virgatum) growth. Analysis of the contaminants and plant biomass was conducted along with microbial enumeration at three soil depths in 49-day intervals. Remediation proceeded rapidly near the surface of the soil (0-20 cm) for both vegetated and unvegetated columns, but the effect of vegetation relative to an unvegetated control only was significant in the lower soil depths. Contaminant dissipation in the 20-40 and 40-60 cm layers was not significantly different between vegetated and unvegetated soil.

Research paper thumbnail of Analysis of oxidative stress in mouse model of cerebral amyloid angiopathy (CAA)

The Faseb Journal, Apr 1, 2009

Research paper thumbnail of Traumatic Brain Injury Alters Synaptic Homeostasis: Implications for Impaired Mitochondrial and Transport Function

Journal of Neurotrauma, Nov 1, 1998

This study utilized a unilateral controlled cortical impact model of traumatic brain injury to as... more This study utilized a unilateral controlled cortical impact model of traumatic brain injury to assess disruptions of synaptic homeostasis following trauma. Adult rats were subjected to a moderate (2 mm) cortical deformation and synaptosomes were prepared from the entire ipsilateral (injured) hemisphere or dissected into different regions (hippocampus, injured cortical area including penumbra, residual hemisphere) at various times postinjury (10 and 30 min, and 1, 6, and 24 h). Synaptosomes from the corresponding regions of the contralateral hemisphere were used as controls to assess alterations in synaptic ATP levels, lipid peroxidation, and glutamate and glucose transport. The results demonstrate significant time-dependent alterations in synaptic homeostasis, which included an immediate reduction in ATP levels, coupled with a significant increase in lipid peroxidation within 30 min postinjury. Lipid peroxidation demonstrated a biphasic response with elevations observed 24 h postinjury, a time at which decreases in glutamate and glucose transport occurred. These results suggest that disruption of synaptic homeostasis is an extremely early event following trauma that should be considered when designing pharmacological interventions.

Research paper thumbnail of Integrin �2 Mediates Selective Metastasis to the Liver

Cancer Res, 2009

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad a... more Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

Research paper thumbnail of Lysophosphatidic Acid Induces Necrosis and Apoptosis in Hippocampal Neurons

Journal of Neurochemistry, 1998

A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA)... more A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA) in the CNS. This study identifies and characterizes the induction of neuronal death by LPA. Treatment of cultured hippocampal neurons from embryonic rat brains with 50 microM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10 microM led to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 microM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 microM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserine, and protection against chromatin condensation, TUNEL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1beta converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 microM LPA. LPA (1 microM) also induced a decrease in mitochondrial membrane potential. Moreover, pretreatment of neurons with cyclosporin A protected against the LPA-induced decrease in mitochondrial membrane potential and neuronal apoptosis. Thus, LPA, at pathophysiological levels, can induce neuronal apoptosis and could thereby participate in neurodegenerative disorders.

Research paper thumbnail of Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain

The Journal of Neuroscience the Official Journal of the Society For Neuroscience, Sep 10, 2003

Research paper thumbnail of Lysophosphatidic Acid Decreases Glutamate and Glucose Uptake by Astrocytes

Research paper thumbnail of Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice

The Journal of Nutritional Biochemistry, 2015

Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies ... more Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies have suggested that EVOO has several health promoting effects that could protect from and decrease the risk of Alzheimer's disease (AD). In this study, we investigated the effect of consumption of EVOO-enriched diet on amyloid- and tau-related pathological alterations that are associated with the progression of AD and cerebral amyloid angiopathy (CAA) in TgSwDI mice. Feeding mice with EVOO-enriched diet for 6months, beginning at an age before amyloid-β (Aβ) accumulation starts, has significantly reduced total Aβ and tau brain levels with a significant improvement in mouse cognitive behavior. This reduction in brain Aβ was explained by the enhanced Aβ clearance pathways and reduced brain production of Aβ via modulation of amyloid-β precursor protein processing. On the other hand, although feeding mice with EVOO-enriched diet for 3months, beginning at an age after Aβ accumulation starts, showed improved clearance across the blood-brain barrier and significant reduction in Aβ levels, it did not affect tau levels or improve cognitive functions of TgSwDI mouse. Collectively, results of this study suggest that the long-term consumption of EVOO-containing diet starting at early age provides a protective effect against AD and its related disorder CAA.

Research paper thumbnail of Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1999

Apolipoprotein E (apoE)-related synthetic peptides, the 22 kDa N-terminal thrombin-cleavage fragm... more Apolipoprotein E (apoE)-related synthetic peptides, the 22 kDa N-terminal thrombin-cleavage fragment of apoE (truncated apoE), and full-length apoE have all been shown to exhibit neurotoxic activity under certain culture conditions. In the present study, protease inhibitors reduced the neurotoxicity and proteolysis of full-length apoE but did not block the toxicity of truncated apoE or a synthetic apoE peptide, suggesting that fragments of apoE may account for its toxicity. Additional experiments demonstrated that both truncated apoE and the apoE peptide elicit an increase in intracellular calcium levels and subsequent death of embryonic rat hippocampal neurons in culture. Similar effects on calcium were found when the apoE peptide was applied to chick sympathetic neurons. The rise in intracellular calcium and the hippocampal cell death caused by the apoE peptide were significantly reduced by receptor-associated protein, removal of extracellular calcium, or administration of the spe...

Research paper thumbnail of Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998

Many cases of autosomal dominant early onset Alzheimer's disease (AD) result from mutations i... more Many cases of autosomal dominant early onset Alzheimer's disease (AD) result from mutations in the gene encoding presenilin-1 (PS-1). PS-1 is an integral membrane protein expressed ubiquitously in neurons throughout the brain in which it is located primarily in endoplasmic reticulum (ER). Although the pathogenic mechanism of PS-1 mutations is unknown, recent findings suggest that PS mutations render neurons vulnerable to apoptosis. Because increasing evidence indicates that mitochondrial alterations contribute to neuronal death in AD, we tested the hypothesis that PS-1 mutations sensitize neurons to mitochondrial failure. PC12 cell lines expressing a PS-1 mutation (L286V) exhibited increased sensitivity to apoptosis induced by 3-nitropropionic acid (3-NP) and malonate, inhibitors of succinate dehydrogenase, compared with control cell lines and lines overexpressing wild-type PS-1. The apoptosis-enhancing action of mutant PS-1 was prevented by antioxidants (propyl gallate and glut...

Research paper thumbnail of Interplay between protein synthesis and degradation in the CNS: physiological and pathological implications

Trends in neurosciences, 2007

Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiologic... more Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiological abnormalities and pathologies in the CNS. This could be because reduced protein turnover leads to bulk intracellular protein accumulation. However, conditions associated with compromised UPS function are also associated with impairments in protein synthesis, and impairment of UPS function is sufficient to inhibit protein synthesis. These data suggest that the toxicity of UPS inhibition need not depend on gross intracellular protein accumulation, and indicate the potential for crosstalk between the UPS and protein-synthesis pathways. In this review, we discuss evidence for interplay between the UPS and protein-synthesis machinery, and outline the implications of this crosstalk for physiological and pathological processes in the CNS.

Research paper thumbnail of Diet and age interactions with regards to cholesterol regulation and brain pathogenesis

Current gerontology and geriatrics research, 2010

Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its num... more Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolem...