Patrizia Fattoretti - Academia.edu (original) (raw)
Papers by Patrizia Fattoretti
Annals of the New York Academy of Sciences, 2000
The etiology and/or the causative events leading to dementing illnesses typical of the third age ... more The etiology and/or the causative events leading to dementing illnesses typical of the third age are still poorly understood. However, an early diagnosis may offer a good opportunity to tackle the problem in due time and, hopefully, to retard the progressive and relentless decline of the senile demented brain. Precocious changes in peripheral cells have been hypothesized to mirror alterations occurring in neurons. 1,2 Conceivably these alterations may constitute potential markers of the risk to develop an age-related dementing pathology. In agreement with this rationale, a consistent proliferation of internal membranes has been reported within the platelets of patients affected by Alzheimer's disease. 1,2 These newly synthesized membranes are supposed to be involved in sequestering the free calcium ions escaping impaired homeostatic mechanisms. 2,3 With the aim of assessing the calcium content in human platelets, we set up a morphometric procedure to verify whether cytochemically evidenced intraplatelet calcium aggregates can be considered as a predictive risk factor of a dementing pathology of the senile brain.
Journal of Alzheimer's Disease, 2016
We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activit... more We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.
Journal of Alzheimer's disease: JAD
The effect of chronic aluminum intake has been investigated in the brain of aged male Wistar rats... more The effect of chronic aluminum intake has been investigated in the brain of aged male Wistar rats to assess the potential role of the accumulation of this metal ion on the development of neurodegenerative features observed in Alzheimer's disease. AlCl3 x 6 H2O (2g/L) was administered to experimental animals for 6 months in the drinking water. The total content of Al (microg/g fresh tissue) was measured by inductively coupled plasma atomic emission spectrometry (ICP-AES), while the content of Cu, Zn and Mn was determined by flame AAS in the prosencephalon + mesencephalon, pons-medulla and cerebellum of control and Al(III)-treated animals. The area occupied by mossy fibres in the CA3 field of the hippocampus was estimated by a computer-assisted morphometric method following Timm's preferential staining. In Al(III)-treated rats the concentration of Cu, Zn and Mn did not increase significantly (p < 0.5) in prosencephalon + mesencephalon, nor in pons-medulla (p < 0.5) except for Cu (p < 0.05) in pons-medulla. In the cerebellum the only significant increase was seen for Zn (p < 0.01) while no change was observed for Cu and Mn. The area occupied by the mossy fibres in the hippocampal CA3 field was significantly increased (+32%) in aged Al(III)-treated rats. Since Cu, Zn and Mn are essential components of the cytosolic and mitochondrial superoxide dismutases, it is possible that the increased content of these ions in aged Al(III)-treated rats represents an increased amount of genetic expression of these antioxidant enzymes. Considering that the positivity to Timm's reaction is based on the presence of free or loosely bound Zn2+ ions within synaptic terminals and that Zn2+ ions are reported to be accumulated by hippocampal neurons when tissue injury occurs, the increased area of the mossy fibres in CA3 field of Al(III)-treated rats could indicate increased hippocampal damage in these animals. Taken together, the present findings indicate that the aging CNS is particularly susceptible to Al(III) toxic effects which may increase the cell load of oxidative stress and may contribute, as an aggravating factor, to the development of neurodegenerative events as observed in Alzheimer's disease.
Molecular Brain Research, 1997
Tachykinins inhibit salt appetite when applied intracranially in a number of brain regions and ma... more Tachykinins inhibit salt appetite when applied intracranially in a number of brain regions and may function as endogenous inhibitors of sodium intake. To test the hypothesis that induced increases in salt appetite might involve disinhibition via a reduction in endogenous tachykinin expression, we used a semi-quantitative in situ hybridization analysis to investigate changes in brain areas expressing Ž . Ž . Ž . preprotachykinin-A PPT-A and preprotachykinin-B PPT-B mRNAs of rats after 1 day of sodium depletion 1d Na dep . PPT-A Ž . Ž . mRNA levels were detected in neurons of the olfactory tubercle Tu , the nucleus of the olfactory tubercle LOT , the dorsal and ventral Ž . Ž . Ž . Ž . caudate-putamen d-CPu and v-CPu , the bed nucleus of the stria terminalis BNST , the medial preoptic area mPOA , the habenula Hb Ž . Ž . and the postero-dorsal part of the amygdala MePD . PPT-B mRNA levels were measured in fundus striati FStr , d-CPu, v-CPu, BNST, Ž . Ž . Ž . mPOA, dorsomedial hypothalamic nucleus DMD , arcuate nucleus Arc , central amygdaloid nucleus CeL , basolateral amygdaloid Ž .
Journal of Histochemistry & Cytochemistry, 2001
S U M M A R Y Immunohistochemistry of Glut3 (45 kD), an integral membrane peptide mediating the t... more S U M M A R Y Immunohistochemistry of Glut3 (45 kD), an integral membrane peptide mediating the transport of glucose in neurons, was carried out in the hippocampus of 3-and 28month-old rats to assess the effect of age on energy metabolism. Free-floating sections of fixed-frozen hippocampi were processed for quantitative immunohistochemistry of Glut3. A rabbit affinity-purified antibody identified Glut3 immunoreactivity. Glut3 staining was intense in neuropil, axons, and dendrites, whereas nerve cell bodies were unstained. With aging, Glut3 reactivity was significantly decreased in the inner molecular layer of the hippocampal dentate gyrus ( Ϫ 46%) and the mossy fibers of the CA3 sector ( Ϫ 34%), whereas the stratum radiatum of CA1 did not show any difference due to age. These data document an age-dependent decrease in Glut3 expression in discrete areas of rat hippocampus. Glut3 constitutes the predominant glucose transporter in neurons and is found abundantly in regions with high synaptic density characterized by frequent bursts of function-adequate metabolic activity. Our findings therefore lend further support to the critical role of an impaired metabolism in age-related brain dysfunctions and disease.
Journal of Alzheimer's Disease, 2016
We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activit... more We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.
Journal of Anatomy, 2016
During ageing, a progressive loss of skeletal muscle mass and a decrease in muscle strength and e... more During ageing, a progressive loss of skeletal muscle mass and a decrease in muscle strength and endurance take place, in the condition termed sarcopenia. The mechanisms of sarcopenia are complex and still unclear; however, it is known that muscle atrophy is associated with a decline in the number and/or efficiency of satellite cells, the main contributors to muscle regeneration. Physical exercise proved beneficial in sarcopenia; however, knowledge of the effect of adapted physical exercise on the myogenic properties of satellite cells in aged muscles is limited. In this study the amount and activation state of satellite cells as well as their proliferation and differentiation potential were assessed in situ by morphology, morphometry and immunocytochemistry at light and transmission electron microscopy on 28-month-old mice submitted to adapted aerobic physical exercise on a treadmill. Sedentary age-matched mice served as controls, and sedentary adult mice were used as a reference for an unperturbed control at an age when the capability of muscle regeneration is still high. The effect of physical exercise in aged muscles was further analysed by comparing the myogenic potential of satellite cells isolated from old running and old sedentary mice using an in vitro system that allows observation of the differentiation process under controlled experimental conditions. The results of this ex vivo and in vitro study demonstrated that adapted physical exercise increases the number and activation of satellite cells as well as their capability to differentiate into structurally and functionally correct myotubes (even though the age-related impairment in myotube formation is not fully reversed): this evidence further supports adapted physical exercise as a powerful, non-pharmacological approach to counteract sarcopenia and the age-related deterioration of satellite cell capabilities even at very advanced age.
Bollettino della Società italiana di biologia sperimentale
Beta-adrenergic receptors from submandibular glands of mice were studied by equilibrium binding e... more Beta-adrenergic receptors from submandibular glands of mice were studied by equilibrium binding experiments. Due to the fact that some discrepancies were previously observed among different author data, we compared two methods for non specific binding substruction, that represents the major source of errors in such experiments. Data were obtained strongly suggesting the presence of multiple population of binding sites and/or negative cooperativity.
Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen, 2004
Journal of neurodevelopmental disorders, 2014
During the neurodevelopmental period, the brain is potentially more susceptible to environmental ... more During the neurodevelopmental period, the brain is potentially more susceptible to environmental exposure to pollutants. The aim was to determine if neonatal exposure to permethrin (PERM) pesticide, at a low dosage that does not produce signs of obvious abnormalities, could represent a risk for the onset of diseases later in the life. Neonatal rats (from postnatal day 6 to 21) were treated daily by gavage with a dose of PERM (34 mg/kg) close to the no-observed-adverse-effect level (NOAEL), and hippocampal morphology and function of synapses were investigated in adulthood. Fear conditioning, passive avoidance and Morris water maze tests were used to assess cognitive skills in rats, whereas electron microscopy analysis was used to investigate hippocampal morphological changes that occurred in adults. In both contextual and tone fear conditioning tests, PERM-treated rats showed a decreased freezing. In the passive avoidance test, the consolidation of the inhibitory avoidance was time-l...
Mechanisms of ageing and development
The hypothesis that modifications in beta-adrenergic receptors may be responsible for age-depende... more The hypothesis that modifications in beta-adrenergic receptors may be responsible for age-dependent change previously observed in vivo, has been investigated. Beta-adrenoceptor characteristics of submandibular glands of mice were studied by using the beta-adrenergic antagonist (-)-[3H]dihydroalprenolol. Data from such studies indicated the presence of two functional populations of binding sites in membrane preparations from young animals, displaying high and low affinity, respectively. Experiments performed on old mice membrane preparations revealed a 50% decrease in the high-affinity population receptor number when compared to the preparations from young animals. However, the affinity did not change significantly with advancing age. With regard to the low-affinity population, no statistically significant changes were observed. From these data it can be reasonably assumed that beta-adrenoceptor alteration during ageing may play a major role in the age-dependent impairment of beta-ad...
Current Pharmaceutical Design, 2013
Alzheimer&amp... more Alzheimer's disease (AD) is a complex degenerative disorder of the brain, associated with a progressive cognitive decline. Age is the main risk factor with almost half of the population above 90 years affected by this pathology. AD and brain aging share common molecular changes, so it has been hypothesized that AD could be a form of accelerated brain aging. In this context, senescenceassociated mechanisms could be a valuable target of investigation both to analyze the causes of this disease and to define therapeutic strategies. Senescent phenotypes of glia and neurons, as well as of peripheral cells, have been described in AD. Much evidence indicate that vascular impairment is a fundamental contributor to AD pathology and platelets are generally considered a key element because they represent the link between amyloid-β (Aβ) deposition, peripheral inflammation and endothelial senescence. Both activated and senescent platelets are a source of Aβ, in addition activated platelets secrete many proinflammatory mediators that could contribute to increased peripheral inflammation and endothelial senescence. Treatments aimed to target peripheral endothelial senescence include antioxidants and some substances, such as aspirin, that modulate platelet aggregation and inflammatory response. Heparin has been proposed as a treatment for senile dementia and exhibits anti-inflammatory action as well as inhibitory effects on Aβ assembly. Identifying peripheral targets for AD treatments could also result advantageous as it would be possible to monitor directly their efficacy. Nevertheless more research is needed to clarify all the different aspects and interactions of blood cells, vascular cells and their secretory products.
Archives of Gerontology and Geriatrics, 1982
Beta-adrenergic receptors were characterized in submandibular glands of ageing mice and old mice ... more Beta-adrenergic receptors were characterized in submandibular glands of ageing mice and old mice grafted with a neonatal thymus. No statistically significant changes of receptor affinity were found in the animal models investigated. On the contrary, receptor density showed a progressive decrease with advancing age. The age-related decrease has been found partially corrected in thymus-grafted old animals, which show a statistically significant recovery of receptor density when compared to their untreated littermates. Receptor modulation can be responsible for the age-related impairment and the thymus-dependent correction of beta-adrenergic responsiveness of submandibular glands previously observed in vivo. Hormonal balance and thyroid hormones, in particular, are suggested as being involved in the ageand thymus-dependent regulation of receptor density. In the accompanying Appendix, we describe the mathematical method used to calculate both specific and nonspecific binding from total binding data.
Archives of Gerontology and Geriatrics, 1985
The influence of the thymus on beta-adrenoceptors has been studied in the brain cortex of mice du... more The influence of the thymus on beta-adrenoceptors has been studied in the brain cortex of mice during developing and aging. Affinity of beta-adrenoceptors shows no statistically significant changes in the various animal models investigated. Receptor density shows a fall in both athymic nude mice and in old normal mice. Receptor density, in particular, decreases progressively with advancing age. It has been demonstrated that thymus exerts a regulatory role in both development and aging, as a neonatal thymic graft is capable of reversing the receptor impairments found in young athymic nude mice and in old normal mice.
Archives of Gerontology and Geriatrics, 1986
Many neuroendocrine functions are altered in old animals and their study may represent important ... more Many neuroendocrine functions are altered in old animals and their study may represent important steps in the understanding of the mechanisms of aging. A deeper insight, however, can be achieved by investigating the responsiveness to stimuli, which may reveal alterations not evident in the unstimulated conditions. At this level of study, many of such impairments have been found to be caused by receptor changes. In the present paper a third level of study is suggested in order to gain evidence of some remote failure of adaptive processes strictly linked to intimate mechanisms of aging. As at the second level of study different receptor characteristics can frequently be found at the basis of age-related alterations of biological responsiveness, at the proposed third level altered capacity of receptor regulation may be hypothesized as responsible for altered cell adaptation following hormone and drug stimuli. Experimental data are given which support this view. The possibility that receptor regulation may be used as an index of aging is suggested. This hypothesis leads to the problem of judging the validity of biological parameters deputed to represent good indices of aging. In order to solve this problem, the potential use of a mathematical model of mortality kinetics is discussed. receptor regulation; aging; mathematical model; indices of aging
Scanning microscopy. Supplement
A computer assisted morphometric method has been elaborated to quantify synaptic vesicles evidenc... more A computer assisted morphometric method has been elaborated to quantify synaptic vesicles evidenced by means of the Zinc-Iodide-Osmium (ZIO) staining procedure in nerve endings of a very discrete area of the cerebellar granular layer: the glomerulus. The following parameters were calculated directly on electron microscopic negatives of 4.67 microns 2 of surface terminal area: number of vesicles per unit area (Na), and per unit volume (Nv), volume density (Vv), average diameter (d) and average volume of the single vesicle (V). Ultrastructural changes taking place at nerve endings also cover synaptic vesicles, thus quantitative studies regarding vesicle population at synaptic regions can be correlated to functional changes occurring in the process of chemical transmission and reflect the plasticity of synaptic junctional zones. Although this histochemical staining method generally is referred to as unspecific, after comparing our data with the available literature reports, we propose that ZIO-positive vesicles could have a physiological significance. These ZIO-positive organelles could take part in the intraterminal homeostatic control of Ca++ ions.
Rejuvenation Research, 2008
The morphofunctional features of synaptic mitochondria, positive to the activity of cytochrome ox... more The morphofunctional features of synaptic mitochondria, positive to the activity of cytochrome oxidase (COX), were investigated in the cerebellar cortex of adult and old monkeys (Macaca fascicularis) to assess the potential age-related changes in the energy metabolism occurring at the neuronal synaptic compartment. The following mitochondrial ultrastructural parameters-numeric density (Nv), volume density (Vv), average volume (V), and average length (Fmax)-were measured by computer-assisted morphometric methods. The ratio (R) area of the COX cytochemical precipitate/area of the mitochondrion was semi-automatically calculated and considered as an estimation of the mitochondrial metabolic competence (MMC), that is, the capacity of single organelles to provide adequate amounts of adenosinetriphosphate. No age-related significant differences were found in any of the ultrastructural parameters taken into account, whereas a significant decrease of R was observed in old animals. In these animals, the quartile distribution of the COX-positive organelles, according to their respective cross-sectional area, showed no significant difference of R when comparing small (I quartile), medium-sized (II quartile), and large (III quartile) mitochondria, while a significant decrease of R was evident in oversized mitochondria (IV quartile). Although our data document an age-related preservation of the morphological features of COX-positive mitochondria in the monkey cerebellum, the significant decrease of R in old animals needs to be considered from the functional standpoint. Since COX is the terminal enzyme of the mitochondrial respiratory chain, the estimation of its activity is regarded as a reliable MMC index; thus our findings, by matching preferential cytochemistry and morphometry, support the hypothesis that the specific functional impairment of enlarged synaptic mitochondria may seriously affect information processing and cell-to-cell communication at synaptic junctional areas with aging.
Rejuvenation Research, 2006
Optical density of MAP2 immunoreactivity (OD), the ratio between the MAP2 stained area/total test... more Optical density of MAP2 immunoreactivity (OD), the ratio between the MAP2 stained area/total test area (area fraction: AF), the total length of MAP2 labeled profiles (TL) and the ratio perimeter/area of the immunostained profiles (pleomorphism index [PI]) were measured by quantitative immunohistochemistry in the brain of rats of different ages. In old rats versus young and adult animals, OD and AF were significantly lower, whereas PI was significantly higher, in dentate gyrus molecular layer, CA1 stratum radiatum and olfactory bulb. These findings lend support to the many converging results on the higher vulnerability to aging of the CNS areas featuring higher plasticity.
Rejuvenation Research, 2006
Synaptic numeric density (Nv), average size (area: S), surface density (Sv) and number of synapse... more Synaptic numeric density (Nv), average size (area: S), surface density (Sv) and number of synapses/neurone (Syn/Neur) were morphometrically measured in frontal (FC) and temporal (TC) cortex of adult and old monkeys. Sv was constant, a clear age-related trend to decrease by Nv and increase by S were observed in both areas investigated. Syn/Neur significantly decreased in TC of aged animals (؊21.1%), whereas FC showed a not significant reduction (؊2.6%). The present data support the hypothesis of an increased sensitivity to deterioration of TC synapses in aged monkeys, which might constitute a predisposing condition to the development of senile plaques. 85
Annals of the New York Academy of Sciences, 2000
The etiology and/or the causative events leading to dementing illnesses typical of the third age ... more The etiology and/or the causative events leading to dementing illnesses typical of the third age are still poorly understood. However, an early diagnosis may offer a good opportunity to tackle the problem in due time and, hopefully, to retard the progressive and relentless decline of the senile demented brain. Precocious changes in peripheral cells have been hypothesized to mirror alterations occurring in neurons. 1,2 Conceivably these alterations may constitute potential markers of the risk to develop an age-related dementing pathology. In agreement with this rationale, a consistent proliferation of internal membranes has been reported within the platelets of patients affected by Alzheimer's disease. 1,2 These newly synthesized membranes are supposed to be involved in sequestering the free calcium ions escaping impaired homeostatic mechanisms. 2,3 With the aim of assessing the calcium content in human platelets, we set up a morphometric procedure to verify whether cytochemically evidenced intraplatelet calcium aggregates can be considered as a predictive risk factor of a dementing pathology of the senile brain.
Journal of Alzheimer's Disease, 2016
We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activit... more We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.
Journal of Alzheimer's disease: JAD
The effect of chronic aluminum intake has been investigated in the brain of aged male Wistar rats... more The effect of chronic aluminum intake has been investigated in the brain of aged male Wistar rats to assess the potential role of the accumulation of this metal ion on the development of neurodegenerative features observed in Alzheimer's disease. AlCl3 x 6 H2O (2g/L) was administered to experimental animals for 6 months in the drinking water. The total content of Al (microg/g fresh tissue) was measured by inductively coupled plasma atomic emission spectrometry (ICP-AES), while the content of Cu, Zn and Mn was determined by flame AAS in the prosencephalon + mesencephalon, pons-medulla and cerebellum of control and Al(III)-treated animals. The area occupied by mossy fibres in the CA3 field of the hippocampus was estimated by a computer-assisted morphometric method following Timm's preferential staining. In Al(III)-treated rats the concentration of Cu, Zn and Mn did not increase significantly (p < 0.5) in prosencephalon + mesencephalon, nor in pons-medulla (p < 0.5) except for Cu (p < 0.05) in pons-medulla. In the cerebellum the only significant increase was seen for Zn (p < 0.01) while no change was observed for Cu and Mn. The area occupied by the mossy fibres in the hippocampal CA3 field was significantly increased (+32%) in aged Al(III)-treated rats. Since Cu, Zn and Mn are essential components of the cytosolic and mitochondrial superoxide dismutases, it is possible that the increased content of these ions in aged Al(III)-treated rats represents an increased amount of genetic expression of these antioxidant enzymes. Considering that the positivity to Timm's reaction is based on the presence of free or loosely bound Zn2+ ions within synaptic terminals and that Zn2+ ions are reported to be accumulated by hippocampal neurons when tissue injury occurs, the increased area of the mossy fibres in CA3 field of Al(III)-treated rats could indicate increased hippocampal damage in these animals. Taken together, the present findings indicate that the aging CNS is particularly susceptible to Al(III) toxic effects which may increase the cell load of oxidative stress and may contribute, as an aggravating factor, to the development of neurodegenerative events as observed in Alzheimer's disease.
Molecular Brain Research, 1997
Tachykinins inhibit salt appetite when applied intracranially in a number of brain regions and ma... more Tachykinins inhibit salt appetite when applied intracranially in a number of brain regions and may function as endogenous inhibitors of sodium intake. To test the hypothesis that induced increases in salt appetite might involve disinhibition via a reduction in endogenous tachykinin expression, we used a semi-quantitative in situ hybridization analysis to investigate changes in brain areas expressing Ž . Ž . Ž . preprotachykinin-A PPT-A and preprotachykinin-B PPT-B mRNAs of rats after 1 day of sodium depletion 1d Na dep . PPT-A Ž . Ž . mRNA levels were detected in neurons of the olfactory tubercle Tu , the nucleus of the olfactory tubercle LOT , the dorsal and ventral Ž . Ž . Ž . Ž . caudate-putamen d-CPu and v-CPu , the bed nucleus of the stria terminalis BNST , the medial preoptic area mPOA , the habenula Hb Ž . Ž . and the postero-dorsal part of the amygdala MePD . PPT-B mRNA levels were measured in fundus striati FStr , d-CPu, v-CPu, BNST, Ž . Ž . Ž . mPOA, dorsomedial hypothalamic nucleus DMD , arcuate nucleus Arc , central amygdaloid nucleus CeL , basolateral amygdaloid Ž .
Journal of Histochemistry & Cytochemistry, 2001
S U M M A R Y Immunohistochemistry of Glut3 (45 kD), an integral membrane peptide mediating the t... more S U M M A R Y Immunohistochemistry of Glut3 (45 kD), an integral membrane peptide mediating the transport of glucose in neurons, was carried out in the hippocampus of 3-and 28month-old rats to assess the effect of age on energy metabolism. Free-floating sections of fixed-frozen hippocampi were processed for quantitative immunohistochemistry of Glut3. A rabbit affinity-purified antibody identified Glut3 immunoreactivity. Glut3 staining was intense in neuropil, axons, and dendrites, whereas nerve cell bodies were unstained. With aging, Glut3 reactivity was significantly decreased in the inner molecular layer of the hippocampal dentate gyrus ( Ϫ 46%) and the mossy fibers of the CA3 sector ( Ϫ 34%), whereas the stratum radiatum of CA1 did not show any difference due to age. These data document an age-dependent decrease in Glut3 expression in discrete areas of rat hippocampus. Glut3 constitutes the predominant glucose transporter in neurons and is found abundantly in regions with high synaptic density characterized by frequent bursts of function-adequate metabolic activity. Our findings therefore lend further support to the critical role of an impaired metabolism in age-related brain dysfunctions and disease.
Journal of Alzheimer's Disease, 2016
We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activit... more We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.
Journal of Anatomy, 2016
During ageing, a progressive loss of skeletal muscle mass and a decrease in muscle strength and e... more During ageing, a progressive loss of skeletal muscle mass and a decrease in muscle strength and endurance take place, in the condition termed sarcopenia. The mechanisms of sarcopenia are complex and still unclear; however, it is known that muscle atrophy is associated with a decline in the number and/or efficiency of satellite cells, the main contributors to muscle regeneration. Physical exercise proved beneficial in sarcopenia; however, knowledge of the effect of adapted physical exercise on the myogenic properties of satellite cells in aged muscles is limited. In this study the amount and activation state of satellite cells as well as their proliferation and differentiation potential were assessed in situ by morphology, morphometry and immunocytochemistry at light and transmission electron microscopy on 28-month-old mice submitted to adapted aerobic physical exercise on a treadmill. Sedentary age-matched mice served as controls, and sedentary adult mice were used as a reference for an unperturbed control at an age when the capability of muscle regeneration is still high. The effect of physical exercise in aged muscles was further analysed by comparing the myogenic potential of satellite cells isolated from old running and old sedentary mice using an in vitro system that allows observation of the differentiation process under controlled experimental conditions. The results of this ex vivo and in vitro study demonstrated that adapted physical exercise increases the number and activation of satellite cells as well as their capability to differentiate into structurally and functionally correct myotubes (even though the age-related impairment in myotube formation is not fully reversed): this evidence further supports adapted physical exercise as a powerful, non-pharmacological approach to counteract sarcopenia and the age-related deterioration of satellite cell capabilities even at very advanced age.
Bollettino della Società italiana di biologia sperimentale
Beta-adrenergic receptors from submandibular glands of mice were studied by equilibrium binding e... more Beta-adrenergic receptors from submandibular glands of mice were studied by equilibrium binding experiments. Due to the fact that some discrepancies were previously observed among different author data, we compared two methods for non specific binding substruction, that represents the major source of errors in such experiments. Data were obtained strongly suggesting the presence of multiple population of binding sites and/or negative cooperativity.
Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen, 2004
Journal of neurodevelopmental disorders, 2014
During the neurodevelopmental period, the brain is potentially more susceptible to environmental ... more During the neurodevelopmental period, the brain is potentially more susceptible to environmental exposure to pollutants. The aim was to determine if neonatal exposure to permethrin (PERM) pesticide, at a low dosage that does not produce signs of obvious abnormalities, could represent a risk for the onset of diseases later in the life. Neonatal rats (from postnatal day 6 to 21) were treated daily by gavage with a dose of PERM (34 mg/kg) close to the no-observed-adverse-effect level (NOAEL), and hippocampal morphology and function of synapses were investigated in adulthood. Fear conditioning, passive avoidance and Morris water maze tests were used to assess cognitive skills in rats, whereas electron microscopy analysis was used to investigate hippocampal morphological changes that occurred in adults. In both contextual and tone fear conditioning tests, PERM-treated rats showed a decreased freezing. In the passive avoidance test, the consolidation of the inhibitory avoidance was time-l...
Mechanisms of ageing and development
The hypothesis that modifications in beta-adrenergic receptors may be responsible for age-depende... more The hypothesis that modifications in beta-adrenergic receptors may be responsible for age-dependent change previously observed in vivo, has been investigated. Beta-adrenoceptor characteristics of submandibular glands of mice were studied by using the beta-adrenergic antagonist (-)-[3H]dihydroalprenolol. Data from such studies indicated the presence of two functional populations of binding sites in membrane preparations from young animals, displaying high and low affinity, respectively. Experiments performed on old mice membrane preparations revealed a 50% decrease in the high-affinity population receptor number when compared to the preparations from young animals. However, the affinity did not change significantly with advancing age. With regard to the low-affinity population, no statistically significant changes were observed. From these data it can be reasonably assumed that beta-adrenoceptor alteration during ageing may play a major role in the age-dependent impairment of beta-ad...
Current Pharmaceutical Design, 2013
Alzheimer&amp... more Alzheimer's disease (AD) is a complex degenerative disorder of the brain, associated with a progressive cognitive decline. Age is the main risk factor with almost half of the population above 90 years affected by this pathology. AD and brain aging share common molecular changes, so it has been hypothesized that AD could be a form of accelerated brain aging. In this context, senescenceassociated mechanisms could be a valuable target of investigation both to analyze the causes of this disease and to define therapeutic strategies. Senescent phenotypes of glia and neurons, as well as of peripheral cells, have been described in AD. Much evidence indicate that vascular impairment is a fundamental contributor to AD pathology and platelets are generally considered a key element because they represent the link between amyloid-β (Aβ) deposition, peripheral inflammation and endothelial senescence. Both activated and senescent platelets are a source of Aβ, in addition activated platelets secrete many proinflammatory mediators that could contribute to increased peripheral inflammation and endothelial senescence. Treatments aimed to target peripheral endothelial senescence include antioxidants and some substances, such as aspirin, that modulate platelet aggregation and inflammatory response. Heparin has been proposed as a treatment for senile dementia and exhibits anti-inflammatory action as well as inhibitory effects on Aβ assembly. Identifying peripheral targets for AD treatments could also result advantageous as it would be possible to monitor directly their efficacy. Nevertheless more research is needed to clarify all the different aspects and interactions of blood cells, vascular cells and their secretory products.
Archives of Gerontology and Geriatrics, 1982
Beta-adrenergic receptors were characterized in submandibular glands of ageing mice and old mice ... more Beta-adrenergic receptors were characterized in submandibular glands of ageing mice and old mice grafted with a neonatal thymus. No statistically significant changes of receptor affinity were found in the animal models investigated. On the contrary, receptor density showed a progressive decrease with advancing age. The age-related decrease has been found partially corrected in thymus-grafted old animals, which show a statistically significant recovery of receptor density when compared to their untreated littermates. Receptor modulation can be responsible for the age-related impairment and the thymus-dependent correction of beta-adrenergic responsiveness of submandibular glands previously observed in vivo. Hormonal balance and thyroid hormones, in particular, are suggested as being involved in the ageand thymus-dependent regulation of receptor density. In the accompanying Appendix, we describe the mathematical method used to calculate both specific and nonspecific binding from total binding data.
Archives of Gerontology and Geriatrics, 1985
The influence of the thymus on beta-adrenoceptors has been studied in the brain cortex of mice du... more The influence of the thymus on beta-adrenoceptors has been studied in the brain cortex of mice during developing and aging. Affinity of beta-adrenoceptors shows no statistically significant changes in the various animal models investigated. Receptor density shows a fall in both athymic nude mice and in old normal mice. Receptor density, in particular, decreases progressively with advancing age. It has been demonstrated that thymus exerts a regulatory role in both development and aging, as a neonatal thymic graft is capable of reversing the receptor impairments found in young athymic nude mice and in old normal mice.
Archives of Gerontology and Geriatrics, 1986
Many neuroendocrine functions are altered in old animals and their study may represent important ... more Many neuroendocrine functions are altered in old animals and their study may represent important steps in the understanding of the mechanisms of aging. A deeper insight, however, can be achieved by investigating the responsiveness to stimuli, which may reveal alterations not evident in the unstimulated conditions. At this level of study, many of such impairments have been found to be caused by receptor changes. In the present paper a third level of study is suggested in order to gain evidence of some remote failure of adaptive processes strictly linked to intimate mechanisms of aging. As at the second level of study different receptor characteristics can frequently be found at the basis of age-related alterations of biological responsiveness, at the proposed third level altered capacity of receptor regulation may be hypothesized as responsible for altered cell adaptation following hormone and drug stimuli. Experimental data are given which support this view. The possibility that receptor regulation may be used as an index of aging is suggested. This hypothesis leads to the problem of judging the validity of biological parameters deputed to represent good indices of aging. In order to solve this problem, the potential use of a mathematical model of mortality kinetics is discussed. receptor regulation; aging; mathematical model; indices of aging
Scanning microscopy. Supplement
A computer assisted morphometric method has been elaborated to quantify synaptic vesicles evidenc... more A computer assisted morphometric method has been elaborated to quantify synaptic vesicles evidenced by means of the Zinc-Iodide-Osmium (ZIO) staining procedure in nerve endings of a very discrete area of the cerebellar granular layer: the glomerulus. The following parameters were calculated directly on electron microscopic negatives of 4.67 microns 2 of surface terminal area: number of vesicles per unit area (Na), and per unit volume (Nv), volume density (Vv), average diameter (d) and average volume of the single vesicle (V). Ultrastructural changes taking place at nerve endings also cover synaptic vesicles, thus quantitative studies regarding vesicle population at synaptic regions can be correlated to functional changes occurring in the process of chemical transmission and reflect the plasticity of synaptic junctional zones. Although this histochemical staining method generally is referred to as unspecific, after comparing our data with the available literature reports, we propose that ZIO-positive vesicles could have a physiological significance. These ZIO-positive organelles could take part in the intraterminal homeostatic control of Ca++ ions.
Rejuvenation Research, 2008
The morphofunctional features of synaptic mitochondria, positive to the activity of cytochrome ox... more The morphofunctional features of synaptic mitochondria, positive to the activity of cytochrome oxidase (COX), were investigated in the cerebellar cortex of adult and old monkeys (Macaca fascicularis) to assess the potential age-related changes in the energy metabolism occurring at the neuronal synaptic compartment. The following mitochondrial ultrastructural parameters-numeric density (Nv), volume density (Vv), average volume (V), and average length (Fmax)-were measured by computer-assisted morphometric methods. The ratio (R) area of the COX cytochemical precipitate/area of the mitochondrion was semi-automatically calculated and considered as an estimation of the mitochondrial metabolic competence (MMC), that is, the capacity of single organelles to provide adequate amounts of adenosinetriphosphate. No age-related significant differences were found in any of the ultrastructural parameters taken into account, whereas a significant decrease of R was observed in old animals. In these animals, the quartile distribution of the COX-positive organelles, according to their respective cross-sectional area, showed no significant difference of R when comparing small (I quartile), medium-sized (II quartile), and large (III quartile) mitochondria, while a significant decrease of R was evident in oversized mitochondria (IV quartile). Although our data document an age-related preservation of the morphological features of COX-positive mitochondria in the monkey cerebellum, the significant decrease of R in old animals needs to be considered from the functional standpoint. Since COX is the terminal enzyme of the mitochondrial respiratory chain, the estimation of its activity is regarded as a reliable MMC index; thus our findings, by matching preferential cytochemistry and morphometry, support the hypothesis that the specific functional impairment of enlarged synaptic mitochondria may seriously affect information processing and cell-to-cell communication at synaptic junctional areas with aging.
Rejuvenation Research, 2006
Optical density of MAP2 immunoreactivity (OD), the ratio between the MAP2 stained area/total test... more Optical density of MAP2 immunoreactivity (OD), the ratio between the MAP2 stained area/total test area (area fraction: AF), the total length of MAP2 labeled profiles (TL) and the ratio perimeter/area of the immunostained profiles (pleomorphism index [PI]) were measured by quantitative immunohistochemistry in the brain of rats of different ages. In old rats versus young and adult animals, OD and AF were significantly lower, whereas PI was significantly higher, in dentate gyrus molecular layer, CA1 stratum radiatum and olfactory bulb. These findings lend support to the many converging results on the higher vulnerability to aging of the CNS areas featuring higher plasticity.
Rejuvenation Research, 2006
Synaptic numeric density (Nv), average size (area: S), surface density (Sv) and number of synapse... more Synaptic numeric density (Nv), average size (area: S), surface density (Sv) and number of synapses/neurone (Syn/Neur) were morphometrically measured in frontal (FC) and temporal (TC) cortex of adult and old monkeys. Sv was constant, a clear age-related trend to decrease by Nv and increase by S were observed in both areas investigated. Syn/Neur significantly decreased in TC of aged animals (؊21.1%), whereas FC showed a not significant reduction (؊2.6%). The present data support the hypothesis of an increased sensitivity to deterioration of TC synapses in aged monkeys, which might constitute a predisposing condition to the development of senile plaques. 85