The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in t... more The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex, are regulated by specific high-affinity Na+/Cl− dependent plasma membrane transporters. Three GABA transporters (GATs), named GAT-1, GAT-2, and GAT-3 appear to play an important role in determining GABA’s effects. Studies on the distribution, cellular and subcellular localization, ontogeny, relationships of GATs with GABA-releasing elements using a variety of light and electron microscopic immunocytochemical techniques, as well as on their physiological effects performed over the last 25 years in our laboratory have contributed to unveil their organizational plan and at least some of their physiological roles. Although many details are missing, the anatomy and physiology of the cortical GABA uptake system in the adult (and developing) cerebral cortex appears to be sufficiently understood to allow the study of its dynamic physiological features, as well as its role in neuropsychiatric diseases.
The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in t... more The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex, are regulated by specific high-affinity Na+/Cl− dependent plasma membrane transporters. Three GABA transporters (GATs), named GAT-1, GAT-2, and GAT-3 appear to play an important role in determining GABA’s effects. Studies on the distribution, cellular and subcellular localization, ontogeny, relationships of GATs with GABA-releasing elements using a variety of light and electron microscopic immunocytochemical techniques, as well as on their physiological effects performed over the last 25 years in our laboratory have contributed to unveil their organizational plan and at least some of their physiological roles. Although many details are missing, the anatomy and physiology of the cortical GABA uptake system in the adult (and developing) cerebral cortex appears to be sufficiently understood to allow the study of its dynamic physiological features, as well as its role in ...
Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interv... more Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interventions in patients with Mild Cognitive Impairment (MCI) is crucial. Cerebral Brain Derived Neurotrophic Factor (BDNF) alterations were evidenced in Alzheimer's disease, but the value of blood BDNF in MCI is unclear, especially because of the incomplete/incorrect management of the numerous confounding factors unrelated to the disease. The present study, applying a multidisciplinary methodological approach, aimed to clarify whether blood BDNF can really mirror the cognitive symptoms of MCI, thus supporting the evaluation of clinical protocols' effectiveness as well as the definition of the conversion rate to dementia. Healthy elderly subjects (HE) and MCI patients were assessed for socio-demographic, neuropsychological, pharmacological and lifestyle data, and plasma BDNF was measured (baseline); then, in the MCI cohort, the biomarker was tested in a comprehensive cognitive stimulation intervention (CS) as well as in a 2-year follow-up period. Plasma BDNF, cleansed from all the interfering factors, i) did not discriminate HE and MCI patients, ii) in MCI patients reflected mood, social engagement, and subjective memory complaints but not cognition, iii) changed due to CS, although with no correlations to cognitive performances, iv) predicted no functional deterioration. Our data indicate that the possible biased use of plasma BDNF in MCI is critically risky.
Advances in Experimental Medicine and Biology, 1999
The brain consists of a complex network in which neurones and glial cells are structurally and fu... more The brain consists of a complex network in which neurones and glial cells are structurally and functionally interwoven. Astrocytes, the most numerous member of the glial family, were originally considered, along with the whole glial population, to be only of structural importance (Virchow, 1846). For example, during development the radial glia, the precursors of astrocytes, serve as a scaffold at which neurones migrate to form the layered structure of different brain regions such as the cortex, the hippocampus or the cerebellum. During the last two decades, considerable knowledge about astrocytes has accumulated regarding their physiological function. One exciting function is their contribution to the regulation of the extracellular space and, thereby, also of brain excitability (Walz, 1989). Qualities such as their capacity for uptake and metabolism of transmitters, buffering capacity of ions and ability to convey external signals via surface receptors to biological responses within the cells indicate an intimate crosstalk between glial cells and neurones. The other major glial population in the brain are the oligodendrocytes. As small cells with few processes they form the myelin sheath, a highly lipid enriched stack of cell membranes enwrapping 50 to 300αm long axonal segments to enhance the conduction of electrical signals and to inhibit electrical crosstalk between individual axons. Oligodendrocytes are capable of myelinating up to 50 axonal segments simultaneously. Mature oligodendrocytes develop from progenitors originating from the subventricular zone as the germinative layer (Miller, 1996). In vertebrates, progenitors start to migrate to their final destination regions, the presumptive white matter, during the first postnatal week.
Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interv... more Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interventions in patients with Mild Cognitive Impairment (MCI) is crucial. Cerebral Brain Derived Neurotrophic Factor (BDNF) alterations were evidenced in Alzheimer's disease, but the value of blood BDNF in MCI is unclear, especially because of the incomplete/incorrect management of the numerous confounding factors unrelated to the disease. The present study, applying a multidisciplinary methodological approach, aimed to clarify whether blood BDNF can really mirror the cognitive symptoms of MCI, thus supporting the evaluation of clinical protocols' effectiveness as well as the definition of the conversion rate to dementia. Healthy elderly subjects (HE) and MCI patients were assessed for socio-demographic, neuropsychological, pharmacological and lifestyle data, and plasma BDNF was measured (baseline); then, in the MCI cohort, the biomarker was tested in a comprehensive cognitive stimulation intervention (CS) as well as in a 2-year follow-up period. Plasma BDNF, cleansed from all the interfering factors, i) did not discriminate HE and MCI patients, ii) in MCI patients reflected mood, social engagement, and subjective memory complaints but not cognition, iii) changed due to CS, although with no correlations to cognitive performances, iv) predicted no functional deterioration. Our data indicate that the possible biased use of plasma BDNF in MCI is critically risky.
Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from ... more Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain. Objective: To generate and characterize the C.B6/J-APPswe mouse, a model of AD with a mutated human gene for the amyloid-β protein precursor (AβPP) inserted in a BALB/c background. Methods: We analyzed five groups at different ages (3, 6, 9, 12, and 16–18 months) of C.B6/J-APPswe and wild-type mice (50% males and 50% females) for the main hallmarks of AD by western blotting, amyloid-β (Aβ) ELISA, immunocytochemistry, electrophysiology, and behavioral tests. Results: The C.B6/J-APPswe mouse displays early AβPP and Aβ production, late amyloid plaques formation, high level of Tau phosphorylation, synaptic deficits (reduced density and functional impairment due to a reduced post-synaptic responsiveness), neurodegeneration caused by apoptosis and necroptosis/necrosis, micr...
Background Recent clinical and experimental studies have highlighted the involvement of Ventral T... more Background Recent clinical and experimental studies have highlighted the involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons for the early pathogenesis of Alzheimer’s Disease (AD). We have previously described a progressive and selective degeneration of these neurons in the Tg2576 mouse model of AD, long before amyloid-beta plaque formation. The degenerative process in DA neurons is associated with an autophagy flux impairment, whose rescue can prevent neuronal loss. Impairments in autophagy can be the basis for accumulation of damaged mitochondria, leading to disturbance in calcium (Ca2+) homeostasis, and to functional and structural deterioration of DA neurons. Methods In Tg2576 mice, we performed amperometric recordings of DA levels and analysis of dopaminergic fibers in the Nucleus Accumbens – a major component of the ventral striatum precociously affected in AD patients – together with retrograde tracing, to identify the most vulnerable DA neuron subpopulations in...
The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in t... more The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex, are regulated by specific high-affinity Na+/Cl− dependent plasma membrane transporters. Three GABA transporters (GATs), named GAT-1, GAT-2, and GAT-3 appear to play an important role in determining GABA’s effects. Studies on the distribution, cellular and subcellular localization, ontogeny, relationships of GATs with GABA-releasing elements using a variety of light and electron microscopic immunocytochemical techniques, as well as on their physiological effects performed over the last 25 years in our laboratory have contributed to unveil their organizational plan and at least some of their physiological roles. Although many details are missing, the anatomy and physiology of the cortical GABA uptake system in the adult (and developing) cerebral cortex appears to be sufficiently understood to allow the study of its dynamic physiological features, as well as its role in neuropsychiatric diseases.
The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in t... more The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex, are regulated by specific high-affinity Na+/Cl− dependent plasma membrane transporters. Three GABA transporters (GATs), named GAT-1, GAT-2, and GAT-3 appear to play an important role in determining GABA’s effects. Studies on the distribution, cellular and subcellular localization, ontogeny, relationships of GATs with GABA-releasing elements using a variety of light and electron microscopic immunocytochemical techniques, as well as on their physiological effects performed over the last 25 years in our laboratory have contributed to unveil their organizational plan and at least some of their physiological roles. Although many details are missing, the anatomy and physiology of the cortical GABA uptake system in the adult (and developing) cerebral cortex appears to be sufficiently understood to allow the study of its dynamic physiological features, as well as its role in ...
Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interv... more Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interventions in patients with Mild Cognitive Impairment (MCI) is crucial. Cerebral Brain Derived Neurotrophic Factor (BDNF) alterations were evidenced in Alzheimer's disease, but the value of blood BDNF in MCI is unclear, especially because of the incomplete/incorrect management of the numerous confounding factors unrelated to the disease. The present study, applying a multidisciplinary methodological approach, aimed to clarify whether blood BDNF can really mirror the cognitive symptoms of MCI, thus supporting the evaluation of clinical protocols' effectiveness as well as the definition of the conversion rate to dementia. Healthy elderly subjects (HE) and MCI patients were assessed for socio-demographic, neuropsychological, pharmacological and lifestyle data, and plasma BDNF was measured (baseline); then, in the MCI cohort, the biomarker was tested in a comprehensive cognitive stimulation intervention (CS) as well as in a 2-year follow-up period. Plasma BDNF, cleansed from all the interfering factors, i) did not discriminate HE and MCI patients, ii) in MCI patients reflected mood, social engagement, and subjective memory complaints but not cognition, iii) changed due to CS, although with no correlations to cognitive performances, iv) predicted no functional deterioration. Our data indicate that the possible biased use of plasma BDNF in MCI is critically risky.
Advances in Experimental Medicine and Biology, 1999
The brain consists of a complex network in which neurones and glial cells are structurally and fu... more The brain consists of a complex network in which neurones and glial cells are structurally and functionally interwoven. Astrocytes, the most numerous member of the glial family, were originally considered, along with the whole glial population, to be only of structural importance (Virchow, 1846). For example, during development the radial glia, the precursors of astrocytes, serve as a scaffold at which neurones migrate to form the layered structure of different brain regions such as the cortex, the hippocampus or the cerebellum. During the last two decades, considerable knowledge about astrocytes has accumulated regarding their physiological function. One exciting function is their contribution to the regulation of the extracellular space and, thereby, also of brain excitability (Walz, 1989). Qualities such as their capacity for uptake and metabolism of transmitters, buffering capacity of ions and ability to convey external signals via surface receptors to biological responses within the cells indicate an intimate crosstalk between glial cells and neurones. The other major glial population in the brain are the oligodendrocytes. As small cells with few processes they form the myelin sheath, a highly lipid enriched stack of cell membranes enwrapping 50 to 300αm long axonal segments to enhance the conduction of electrical signals and to inhibit electrical crosstalk between individual axons. Oligodendrocytes are capable of myelinating up to 50 axonal segments simultaneously. Mature oligodendrocytes develop from progenitors originating from the subventricular zone as the germinative layer (Miller, 1996). In vertebrates, progenitors start to migrate to their final destination regions, the presumptive white matter, during the first postnatal week.
Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interv... more Availability of reliable prognostic biomarkers also able to monitor preventive/therapeutic interventions in patients with Mild Cognitive Impairment (MCI) is crucial. Cerebral Brain Derived Neurotrophic Factor (BDNF) alterations were evidenced in Alzheimer's disease, but the value of blood BDNF in MCI is unclear, especially because of the incomplete/incorrect management of the numerous confounding factors unrelated to the disease. The present study, applying a multidisciplinary methodological approach, aimed to clarify whether blood BDNF can really mirror the cognitive symptoms of MCI, thus supporting the evaluation of clinical protocols' effectiveness as well as the definition of the conversion rate to dementia. Healthy elderly subjects (HE) and MCI patients were assessed for socio-demographic, neuropsychological, pharmacological and lifestyle data, and plasma BDNF was measured (baseline); then, in the MCI cohort, the biomarker was tested in a comprehensive cognitive stimulation intervention (CS) as well as in a 2-year follow-up period. Plasma BDNF, cleansed from all the interfering factors, i) did not discriminate HE and MCI patients, ii) in MCI patients reflected mood, social engagement, and subjective memory complaints but not cognition, iii) changed due to CS, although with no correlations to cognitive performances, iv) predicted no functional deterioration. Our data indicate that the possible biased use of plasma BDNF in MCI is critically risky.
Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from ... more Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain. Objective: To generate and characterize the C.B6/J-APPswe mouse, a model of AD with a mutated human gene for the amyloid-β protein precursor (AβPP) inserted in a BALB/c background. Methods: We analyzed five groups at different ages (3, 6, 9, 12, and 16–18 months) of C.B6/J-APPswe and wild-type mice (50% males and 50% females) for the main hallmarks of AD by western blotting, amyloid-β (Aβ) ELISA, immunocytochemistry, electrophysiology, and behavioral tests. Results: The C.B6/J-APPswe mouse displays early AβPP and Aβ production, late amyloid plaques formation, high level of Tau phosphorylation, synaptic deficits (reduced density and functional impairment due to a reduced post-synaptic responsiveness), neurodegeneration caused by apoptosis and necroptosis/necrosis, micr...
Background Recent clinical and experimental studies have highlighted the involvement of Ventral T... more Background Recent clinical and experimental studies have highlighted the involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons for the early pathogenesis of Alzheimer’s Disease (AD). We have previously described a progressive and selective degeneration of these neurons in the Tg2576 mouse model of AD, long before amyloid-beta plaque formation. The degenerative process in DA neurons is associated with an autophagy flux impairment, whose rescue can prevent neuronal loss. Impairments in autophagy can be the basis for accumulation of damaged mitochondria, leading to disturbance in calcium (Ca2+) homeostasis, and to functional and structural deterioration of DA neurons. Methods In Tg2576 mice, we performed amperometric recordings of DA levels and analysis of dopaminergic fibers in the Nucleus Accumbens – a major component of the ventral striatum precociously affected in AD patients – together with retrograde tracing, to identify the most vulnerable DA neuron subpopulations in...
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