Ivona Brasnjevic - Academia.edu (original) (raw)
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Papers by Ivona Brasnjevic
Journal of Chemical Neuroanatomy, 2006
Alzheimers & Dementia, 2006
Brain Structure & Function, 2010
Hippocampal atrophy and neuron loss are commonly found in Alzheimer’s disease (AD). However, the ... more Hippocampal atrophy and neuron loss are commonly found in Alzheimer’s disease (AD). However, the underlying molecular mechanisms and the fate in the AD hippocampus of subpopulations of interneurons that express the calcium-binding proteins parvalbumin (PV) and calretinin (CR) has not yet been properly assessed. Using quantitative stereologic methods, we analyzed the regional pattern of age-related loss of PV- and CR-immunoreactive (ir) neurons in the hippocampus of mice that carry M233T/L235P knocked-in mutations in presenilin-1 (PS1) and overexpress a mutated human beta-amyloid precursor protein (APP), namely, the APPSL/PS1 KI mice, as well as in APPSL mice and PS1 KI mice. We found a loss of PV-ir neurons (40–50%) in the CA1-2, and a loss of CR-ir neurons (37–52%) in the dentate gyrus and hilus of APPSL/PS1 KI mice. Interestingly, comparable PV- and CR-ir neuron losses were observed in the dentate gyrus of postmortem brain specimens obtained from patients with AD. The loss of these interneurons in AD may have substantial functional repercussions on local inhibitory processes in the hippocampus.
Neurobiology of Aging, 2006
In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney prov... more In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney provide an overview on the neuropathology of Alzheimer's disease (AD), genes related to AD, transgenic animal models of AD, and results from studies which have focused on alterations in gene expression in AD, performed both on postmortem brains from patients with AD and controls as well as on transgenic mouse models of this disease. Their major conclusion is that findings from studies carried out to date on alterations in gene expression in AD are still limited in terms of their utility in treating AD patients and in developing early methods of detection. We generally agree with most of the ideas and trajectories of Reddy and McWeeney . However, we would like to draw attention to the following issues.
Mechanisms of Ageing and Development, 2010
Caloric restriction (CR) and antioxidants have been proposed as strategies to attenuate age-relat... more Caloric restriction (CR) and antioxidants have been proposed as strategies to attenuate age-related brain changes. The hippocampus and its subregions dentate gyrus (DG), CA3 and CA1-2 show vulnerability to aging, with hippocampal volume alterations as a measurable sign. Using design-based stereological techniques, we investigated the volumes of the hippocampus and its subregions in six 12-month-old and six 24-month-old mice that were randomly selected from four aging cohorts of 60 male mice each: (1) wild-type mice (WT) fed with control diet (CD), (2) transgenic mice oxerexpressing normal human SOD1 fed with CD, (3) WT mice fed with CR diet, and (4) SOD1 mice fed with CR diet. Aging reduced the mean volume of the entire hippocampus (-9.5%), grey (-8.7%) and white matter (-9.7%), and CA3 subregion (-13.6%), but not DG or CA1-2 subregion. CR reduced the mean volumes of every hippocampal region investigated (on average -11%) in both 12-month-old, and 24-month-old mice. Overexpression of SOD1 was not associated with any volume alteration. These findings indicate that although aging and CR in mice are both associated with hippocampal volume reductions, the patterns of the volume reductions differ. These morphometric alterations may have impact on the function of the hippocampus during aging and CR.
Alzheimers & Dementia, 2006
Acta Neuropathologica, 2007
Pathological effects of moderate ischemia (oligemia, hypoperfusion) are relevant in relation to v... more Pathological effects of moderate ischemia (oligemia, hypoperfusion) are relevant in relation to vascular factors in dementia. Chronic bilateral common carotid artery occlusion (BCCAO) in adult Wistar rats induces oligemia and leads to acute changes in gene expression, subacute changes in cortical astrocytes and prolonged changes in white matter tracts, while largely sparing neurons in the forebrain areas. Dilation and remodeling of the basilar artery ensures blood flow to the forebrain. The present study examined the hypoxia-sensitive Purkinje cells in the cerebellum after 6 months of BCCAO using conventional neuropathological analysis, immunohistochemistry and high-precision design-based stereologic methods. Purkinje cells in the vermis region revealed abnormally shaped nuclei. A stereologic analysis showed that the mean total number of Purkinje cells within the vermis was statistically significantly smaller in the BCCAO animals than in the control animals (d = 11.8%; P
Progress in Neurobiology, 2009
A B S T R A C T Peptide and protein (P/P) drugs have been identified as showing great promises fo... more A B S T R A C T Peptide and protein (P/P) drugs have been identified as showing great promises for the treatment of various neurodegenerative diseases. A major challenge in this regard, however, is the delivery of P/P drugs over the blood-brain barrier (BBB). Intense research over the last 25 years has enabled a better understanding of the cellular and molecular transport mechanisms at the BBB, and several strategies for enhanced P/P drug delivery over the BBB have been developed and tested in preclinical and clinicalexperimental research. Among them, technology-based approaches (comprising functionalized nanocarriers and liposomes) and pharmacological strategies (such as the use of carrier systems and chimeric peptide technology) appear to be the most promising ones. This review combines a comprehensive overview on the current understanding of the transport mechanisms at the BBB with promising selected strategies published so far that can be applied to facilitate enhanced P/P drug delivery over the BBB. ß
Dna Repair, 2008
According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DN... more According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.
Journal of Chemical Neuroanatomy, 2006
Alzheimers & Dementia, 2006
Brain Structure & Function, 2010
Hippocampal atrophy and neuron loss are commonly found in Alzheimer’s disease (AD). However, the ... more Hippocampal atrophy and neuron loss are commonly found in Alzheimer’s disease (AD). However, the underlying molecular mechanisms and the fate in the AD hippocampus of subpopulations of interneurons that express the calcium-binding proteins parvalbumin (PV) and calretinin (CR) has not yet been properly assessed. Using quantitative stereologic methods, we analyzed the regional pattern of age-related loss of PV- and CR-immunoreactive (ir) neurons in the hippocampus of mice that carry M233T/L235P knocked-in mutations in presenilin-1 (PS1) and overexpress a mutated human beta-amyloid precursor protein (APP), namely, the APPSL/PS1 KI mice, as well as in APPSL mice and PS1 KI mice. We found a loss of PV-ir neurons (40–50%) in the CA1-2, and a loss of CR-ir neurons (37–52%) in the dentate gyrus and hilus of APPSL/PS1 KI mice. Interestingly, comparable PV- and CR-ir neuron losses were observed in the dentate gyrus of postmortem brain specimens obtained from patients with AD. The loss of these interneurons in AD may have substantial functional repercussions on local inhibitory processes in the hippocampus.
Neurobiology of Aging, 2006
In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney prov... more In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney provide an overview on the neuropathology of Alzheimer's disease (AD), genes related to AD, transgenic animal models of AD, and results from studies which have focused on alterations in gene expression in AD, performed both on postmortem brains from patients with AD and controls as well as on transgenic mouse models of this disease. Their major conclusion is that findings from studies carried out to date on alterations in gene expression in AD are still limited in terms of their utility in treating AD patients and in developing early methods of detection. We generally agree with most of the ideas and trajectories of Reddy and McWeeney . However, we would like to draw attention to the following issues.
Mechanisms of Ageing and Development, 2010
Caloric restriction (CR) and antioxidants have been proposed as strategies to attenuate age-relat... more Caloric restriction (CR) and antioxidants have been proposed as strategies to attenuate age-related brain changes. The hippocampus and its subregions dentate gyrus (DG), CA3 and CA1-2 show vulnerability to aging, with hippocampal volume alterations as a measurable sign. Using design-based stereological techniques, we investigated the volumes of the hippocampus and its subregions in six 12-month-old and six 24-month-old mice that were randomly selected from four aging cohorts of 60 male mice each: (1) wild-type mice (WT) fed with control diet (CD), (2) transgenic mice oxerexpressing normal human SOD1 fed with CD, (3) WT mice fed with CR diet, and (4) SOD1 mice fed with CR diet. Aging reduced the mean volume of the entire hippocampus (-9.5%), grey (-8.7%) and white matter (-9.7%), and CA3 subregion (-13.6%), but not DG or CA1-2 subregion. CR reduced the mean volumes of every hippocampal region investigated (on average -11%) in both 12-month-old, and 24-month-old mice. Overexpression of SOD1 was not associated with any volume alteration. These findings indicate that although aging and CR in mice are both associated with hippocampal volume reductions, the patterns of the volume reductions differ. These morphometric alterations may have impact on the function of the hippocampus during aging and CR.
Alzheimers & Dementia, 2006
Acta Neuropathologica, 2007
Pathological effects of moderate ischemia (oligemia, hypoperfusion) are relevant in relation to v... more Pathological effects of moderate ischemia (oligemia, hypoperfusion) are relevant in relation to vascular factors in dementia. Chronic bilateral common carotid artery occlusion (BCCAO) in adult Wistar rats induces oligemia and leads to acute changes in gene expression, subacute changes in cortical astrocytes and prolonged changes in white matter tracts, while largely sparing neurons in the forebrain areas. Dilation and remodeling of the basilar artery ensures blood flow to the forebrain. The present study examined the hypoxia-sensitive Purkinje cells in the cerebellum after 6 months of BCCAO using conventional neuropathological analysis, immunohistochemistry and high-precision design-based stereologic methods. Purkinje cells in the vermis region revealed abnormally shaped nuclei. A stereologic analysis showed that the mean total number of Purkinje cells within the vermis was statistically significantly smaller in the BCCAO animals than in the control animals (d = 11.8%; P
Progress in Neurobiology, 2009
A B S T R A C T Peptide and protein (P/P) drugs have been identified as showing great promises fo... more A B S T R A C T Peptide and protein (P/P) drugs have been identified as showing great promises for the treatment of various neurodegenerative diseases. A major challenge in this regard, however, is the delivery of P/P drugs over the blood-brain barrier (BBB). Intense research over the last 25 years has enabled a better understanding of the cellular and molecular transport mechanisms at the BBB, and several strategies for enhanced P/P drug delivery over the BBB have been developed and tested in preclinical and clinicalexperimental research. Among them, technology-based approaches (comprising functionalized nanocarriers and liposomes) and pharmacological strategies (such as the use of carrier systems and chimeric peptide technology) appear to be the most promising ones. This review combines a comprehensive overview on the current understanding of the transport mechanisms at the BBB with promising selected strategies published so far that can be applied to facilitate enhanced P/P drug delivery over the BBB. ß
Dna Repair, 2008
According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DN... more According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.