Maria Rosanna Bronzuoli | Università degli Studi "La Sapienza" di Roma (original) (raw)

Papers by Maria Rosanna Bronzuoli

Frontiers in Pharmacology, 2019

Old age is a risk factor for Alzheimer's disease (AD), which is characterized by hippocampal impa... more Old age is a risk factor for Alzheimer's disease (AD), which is characterized by hippocampal impairment together with substantial changes in glial cell functions. Are these alterations due to the disease progression or are they a consequence of aging? To start addressing this issue, we studied the expression of specific astrocytic and microglial structural and functional proteins in a validated transgenic model of AD (3×Tg-AD). These mice develop both amyloid plaques and neurofibrillary tangles, and initial signs of the AD-like pathology have been documented as early as three months of age. We compared male 3×Tg-AD mice at 6 and 12 months of age with their wild-type age-matched counterparts. We also investigated neurons by examining the expression of both the microtubule-associated protein 2 (MAP2), a neuronal structural protein, and the brain-derived neurotrophic factor (BDNF). The latter is indeed a crucial indicator for synaptic plasticity and neurogenesis/ neurodegeneration. Our results show that astrocytes are more susceptible to aging than microglia, regardless of mouse genotype. Moreover, we discovered significant age-dependent alterations in the expression of proteins responsible for astrocyte-astrocyte and astrocyte-neuron communication, as well as a significant age-dependent decline in BDNF expression. Our data promote further research on the unexplored role of astroglia in both physiological and pathological aging.

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic ... more In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Currenttreatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underliethe decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires amultitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy thatcan be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old)3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Micewere tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magneticresonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potentialneuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chainreaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, andameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβformation,the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus.Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrainsneuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an earlytreatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potentialto be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is alreadyregistered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.

Alzheimer’s disease (AD) is a neurodegenerative disorder responsible for the majority of dementia... more Alzheimer’s disease (AD) is a neurodegenerative disorder responsible for the majority of dementia cases in elderly people. It is widely accepted that the main hallmarks of AD are not only senile plaques and neurofibrillary tangles but also reactive astrogliosis, which often precedes detrimental deposits and neuronal atrophy. Such phenomenon facilitates the regeneration of neural networks; however, under some circumstances, like in AD, reactive astrogliosis is detrimental, depriving neurons of the homeostatic support, thus contributing to neuronal loss. We investigated the presence of reactive astrogliosis in 3×Tg-AD mice and the effects of palmitoylethanolamide (PEA), a well-documented anti-inflammatory molecule, by in vitro and in vivo studies. In vitro results revealed a basal reactive state in primary cortical 3×Tg-AD-derived astrocytes and the ability of PEA to counteract such phenomenon and improve viability of 3×Tg-AD-derived neurons. In vivo observations, performed using ultramicronized- (um-) PEA, a formulation endowed with best bioavailability, confirmed the efficacy of this compound. Moreover, the schedule of treatment, mimicking the clinic use (chronic daily administration), revealed its beneficial pharmacological properties in dampening reactive astrogliosis and promoting the glial neurosupportive function. Collectively, our results encourage further investigation on PEA effects, suggesting it as an alternative or adjunct treatment approach for innovative AD therapy.

Current Pharmaceutical Design, 2017

Alzheimer';s disease is a devastating neurological illness with a heavy economic impact. Further ... more Alzheimer';s disease is a devastating neurological illness with a heavy economic impact. Further comorbidity in combination with the social impact of this disorder increases the urgency of a clearer comprehension of its etiopathogenesis, allowing the execution of novel therapeutic strategies. Despite astrocytes have been widely described as active participant in the regulation of cerebral circuits, available data are still poor. Even less information is available about their precise role in the pathogenesis of illness. Moreover, the scant knowledge about the astrocyte-neuron interplay in health and disease still impede pioneering discoveries. The focus of this review is to look for new and innovative pharmacological approaches against AD. In order to perform this, we used following keywords in PubMed search engine: astrocytes, therapy, Alzheimer's disease, AD, treatment and glia in different combinations. With this review, we collected data available in literature describing how also astrocytes besides neurons might be new potential targets for drug discovery. Different approaches currently being studied include modulation of glutamate transporters expression, astroglial genetic manipulation, free radicals inhibition, up-regulation of neurotrophins, and regulation of astrogliosis and neuroinflammation. Since several studies already demonstrated that astrocytes are definitely involved in AD pathogenesis, these cells can represent a promising new therapeutic target.

Cell Death and Disease, 2014

Given the complex heterogeneity of pathological changes occurring in Alzheimer's disease (AD), an... more Given the complex heterogeneity of pathological changes occurring in Alzheimer's disease (AD), any therapeutic effort absolutely requires a multi-targeted approach, because attempts addressing only a single event may result ineffective. Palmitoylethanolamide (PEA), a naturally occurring lipid amide between palmitic acid and ethanolamine, seems to be a compound able to fulfill the criteria of a multi-factorial therapeutic approach. Here, we describe the anti-inflammatory and neuroprotective activities of systemic administration of PEA in adult male rats given intrahippocampal injection of beta amyloid 1-42 (Aβ 1-42). Moreover, to investigate the molecular mechanisms responsible for the effects induced by PEA, we co-administered PEA with the GW6471, an antagonist of peroxisome proliferator-activated receptor-α (PPAR-α). We found that Aβ 1-42 infusion results in severe changes of biochemical markers related to reactive gliosis, amyloidogenesis, and tau protein hyperphosphorylation. Interestingly, PEA was able to restore the Aβ 1-42-induced alterations through PPAR-α involvement. In addition, results from the Morris water maze task highlighted a mild cognitive deficit during the reversal learning phase of the behavioral study. Similarly to the biochemical data, also mnestic deficits were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, and suggest novel strategies that hopefully could have the potential not just to alleviate the symptoms but also to modify disease progression.

Journal of Inflammation Research, 2016

Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed eve... more Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer's disease (AD) accounts for approximately 60%-80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder.

Frontiers in Neuroscience, 2015

Data from animal models and Alzheimer's disease (AD) subjects provide clear evidence for an activ... more Data from animal models and Alzheimer's disease (AD) subjects provide clear evidence for an activation of inflammatory pathways during the pathogenetic course of such illness. Biochemical and neuropathological studies highlighted an important cause/effect relationship between inflammation and AD progression, revealing a wide range of genetic, cellular, and molecular changes associated with the pathology. In this context, glial cells have been proved to exert a crucial role. These cells, in fact, undergo important morphological and functional changes and are now considered to be involved in the onset and progression of AD. In particular, astrocytes respond quickly to pathology with changes that have been increasingly recognized as a continuum, with potentially beneficial and/or negative consequences. Although it is now clear that activated astrocytes trigger the neuroinflammatory process, however, the precise mechanisms have not been completely elucidated. Neuroinflammation is certainly a multi-faceted and complex phenomenon and, especially in the early stages, exerts a reparative intent. However, for reasons not yet all well known, this process goes beyond the physiologic control and contributes to the exacerbation of the damage. Here we scrutinize some evidence supporting the role of astrocytes in the neuroinflammatory process and the possibility that these cells could be considered a promising target for future AD therapies.

Frontiers in Pharmacology, 2014

Among neurodegenerative disorders, Alzheimer's disease (AD) represents the most common cause of d... more Among neurodegenerative disorders, Alzheimer's disease (AD) represents the most common cause of dementia in the elderly. Several genetic and environmental factors have been identified; however, aging represents the most important risk factor in the development of AD. To date, no effective treatments to prevent or slow this dementia are available. Sirtuins (SIRTs) are a family of NAD(+)-dependent enzymes, implicated in the control of a variety of biological processes that have the potential to modulate neurodegeneration. Here we tested the hypothesis that activation of SIRT1 or inhibition of SIRT2 would prevent reactive gliosis which is considered one of the most important hallmark of AD. Primary rat astrocytes were activated with beta amyloid 1-42 (Aβ 1-42) and treated with resveratrol (RSV) or AGK-2, a SIRT1 activator and a SIRT2-selective inhibitor, respectively. Results showed that both RSV and AGK-2 were able to reduce astrocyte activation as well as the production of pro-inflammatory mediators. These data disclose novel findings about the therapeutic potential of SIRT modulators, and suggest novel strategies for AD treatment.

Books by Maria Rosanna Bronzuoli

The intrahippocampal injection of amyloid beta peptide (1–42) (Aβ(1–42)) represents one of the mo... more The intrahippocampal injection of amyloid beta peptide (1–42) (Aβ(1–42)) represents one of the most useful animal models of Alzheimer disease. Since none of these available models fully represents the main pathological hallmarks of Alzheimer disease, stereotaxic Aβ(1–42) infusion provides researchers with an in vivo alternative paradigm. When performed by well-trained individuals, this model is the best-suited one for short-term studies focusing on the effects of Aβ(1–42) on a specific brain region or circuitry. Here, we describe all methodological phases of such a model.

Hippocampal organotypic cultures constitute a very easy but delicate method widely used to study ... more Hippocampal organotypic cultures constitute a very easy but delicate method widely used to study amyloid
β-peptide toxicity. This ex vivo technique is performed on tissues isolated from newborn rats. Here, we
describe a protocol for the preparation and culture of hippocampal organotypic slices that can be maintained
for 14–21 days and their application to the study of amyloid β-peptide toxicity.

Frontiers in Pharmacology, 2019

Old age is a risk factor for Alzheimer's disease (AD), which is characterized by hippocampal impa... more Old age is a risk factor for Alzheimer's disease (AD), which is characterized by hippocampal impairment together with substantial changes in glial cell functions. Are these alterations due to the disease progression or are they a consequence of aging? To start addressing this issue, we studied the expression of specific astrocytic and microglial structural and functional proteins in a validated transgenic model of AD (3×Tg-AD). These mice develop both amyloid plaques and neurofibrillary tangles, and initial signs of the AD-like pathology have been documented as early as three months of age. We compared male 3×Tg-AD mice at 6 and 12 months of age with their wild-type age-matched counterparts. We also investigated neurons by examining the expression of both the microtubule-associated protein 2 (MAP2), a neuronal structural protein, and the brain-derived neurotrophic factor (BDNF). The latter is indeed a crucial indicator for synaptic plasticity and neurogenesis/ neurodegeneration. Our results show that astrocytes are more susceptible to aging than microglia, regardless of mouse genotype. Moreover, we discovered significant age-dependent alterations in the expression of proteins responsible for astrocyte-astrocyte and astrocyte-neuron communication, as well as a significant age-dependent decline in BDNF expression. Our data promote further research on the unexplored role of astroglia in both physiological and pathological aging.

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic ... more In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Currenttreatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underliethe decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires amultitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy thatcan be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old)3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Micewere tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magneticresonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potentialneuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chainreaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, andameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβformation,the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus.Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrainsneuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an earlytreatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potentialto be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is alreadyregistered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.

Alzheimer’s disease (AD) is a neurodegenerative disorder responsible for the majority of dementia... more Alzheimer’s disease (AD) is a neurodegenerative disorder responsible for the majority of dementia cases in elderly people. It is widely accepted that the main hallmarks of AD are not only senile plaques and neurofibrillary tangles but also reactive astrogliosis, which often precedes detrimental deposits and neuronal atrophy. Such phenomenon facilitates the regeneration of neural networks; however, under some circumstances, like in AD, reactive astrogliosis is detrimental, depriving neurons of the homeostatic support, thus contributing to neuronal loss. We investigated the presence of reactive astrogliosis in 3×Tg-AD mice and the effects of palmitoylethanolamide (PEA), a well-documented anti-inflammatory molecule, by in vitro and in vivo studies. In vitro results revealed a basal reactive state in primary cortical 3×Tg-AD-derived astrocytes and the ability of PEA to counteract such phenomenon and improve viability of 3×Tg-AD-derived neurons. In vivo observations, performed using ultramicronized- (um-) PEA, a formulation endowed with best bioavailability, confirmed the efficacy of this compound. Moreover, the schedule of treatment, mimicking the clinic use (chronic daily administration), revealed its beneficial pharmacological properties in dampening reactive astrogliosis and promoting the glial neurosupportive function. Collectively, our results encourage further investigation on PEA effects, suggesting it as an alternative or adjunct treatment approach for innovative AD therapy.

Current Pharmaceutical Design, 2017

Alzheimer';s disease is a devastating neurological illness with a heavy economic impact. Further ... more Alzheimer';s disease is a devastating neurological illness with a heavy economic impact. Further comorbidity in combination with the social impact of this disorder increases the urgency of a clearer comprehension of its etiopathogenesis, allowing the execution of novel therapeutic strategies. Despite astrocytes have been widely described as active participant in the regulation of cerebral circuits, available data are still poor. Even less information is available about their precise role in the pathogenesis of illness. Moreover, the scant knowledge about the astrocyte-neuron interplay in health and disease still impede pioneering discoveries. The focus of this review is to look for new and innovative pharmacological approaches against AD. In order to perform this, we used following keywords in PubMed search engine: astrocytes, therapy, Alzheimer's disease, AD, treatment and glia in different combinations. With this review, we collected data available in literature describing how also astrocytes besides neurons might be new potential targets for drug discovery. Different approaches currently being studied include modulation of glutamate transporters expression, astroglial genetic manipulation, free radicals inhibition, up-regulation of neurotrophins, and regulation of astrogliosis and neuroinflammation. Since several studies already demonstrated that astrocytes are definitely involved in AD pathogenesis, these cells can represent a promising new therapeutic target.

Cell Death and Disease, 2014

Given the complex heterogeneity of pathological changes occurring in Alzheimer's disease (AD), an... more Given the complex heterogeneity of pathological changes occurring in Alzheimer's disease (AD), any therapeutic effort absolutely requires a multi-targeted approach, because attempts addressing only a single event may result ineffective. Palmitoylethanolamide (PEA), a naturally occurring lipid amide between palmitic acid and ethanolamine, seems to be a compound able to fulfill the criteria of a multi-factorial therapeutic approach. Here, we describe the anti-inflammatory and neuroprotective activities of systemic administration of PEA in adult male rats given intrahippocampal injection of beta amyloid 1-42 (Aβ 1-42). Moreover, to investigate the molecular mechanisms responsible for the effects induced by PEA, we co-administered PEA with the GW6471, an antagonist of peroxisome proliferator-activated receptor-α (PPAR-α). We found that Aβ 1-42 infusion results in severe changes of biochemical markers related to reactive gliosis, amyloidogenesis, and tau protein hyperphosphorylation. Interestingly, PEA was able to restore the Aβ 1-42-induced alterations through PPAR-α involvement. In addition, results from the Morris water maze task highlighted a mild cognitive deficit during the reversal learning phase of the behavioral study. Similarly to the biochemical data, also mnestic deficits were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, and suggest novel strategies that hopefully could have the potential not just to alleviate the symptoms but also to modify disease progression.

Journal of Inflammation Research, 2016

Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed eve... more Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer's disease (AD) accounts for approximately 60%-80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder.

Frontiers in Neuroscience, 2015

Data from animal models and Alzheimer's disease (AD) subjects provide clear evidence for an activ... more Data from animal models and Alzheimer's disease (AD) subjects provide clear evidence for an activation of inflammatory pathways during the pathogenetic course of such illness. Biochemical and neuropathological studies highlighted an important cause/effect relationship between inflammation and AD progression, revealing a wide range of genetic, cellular, and molecular changes associated with the pathology. In this context, glial cells have been proved to exert a crucial role. These cells, in fact, undergo important morphological and functional changes and are now considered to be involved in the onset and progression of AD. In particular, astrocytes respond quickly to pathology with changes that have been increasingly recognized as a continuum, with potentially beneficial and/or negative consequences. Although it is now clear that activated astrocytes trigger the neuroinflammatory process, however, the precise mechanisms have not been completely elucidated. Neuroinflammation is certainly a multi-faceted and complex phenomenon and, especially in the early stages, exerts a reparative intent. However, for reasons not yet all well known, this process goes beyond the physiologic control and contributes to the exacerbation of the damage. Here we scrutinize some evidence supporting the role of astrocytes in the neuroinflammatory process and the possibility that these cells could be considered a promising target for future AD therapies.

Frontiers in Pharmacology, 2014

Among neurodegenerative disorders, Alzheimer's disease (AD) represents the most common cause of d... more Among neurodegenerative disorders, Alzheimer's disease (AD) represents the most common cause of dementia in the elderly. Several genetic and environmental factors have been identified; however, aging represents the most important risk factor in the development of AD. To date, no effective treatments to prevent or slow this dementia are available. Sirtuins (SIRTs) are a family of NAD(+)-dependent enzymes, implicated in the control of a variety of biological processes that have the potential to modulate neurodegeneration. Here we tested the hypothesis that activation of SIRT1 or inhibition of SIRT2 would prevent reactive gliosis which is considered one of the most important hallmark of AD. Primary rat astrocytes were activated with beta amyloid 1-42 (Aβ 1-42) and treated with resveratrol (RSV) or AGK-2, a SIRT1 activator and a SIRT2-selective inhibitor, respectively. Results showed that both RSV and AGK-2 were able to reduce astrocyte activation as well as the production of pro-inflammatory mediators. These data disclose novel findings about the therapeutic potential of SIRT modulators, and suggest novel strategies for AD treatment.

The intrahippocampal injection of amyloid beta peptide (1–42) (Aβ(1–42)) represents one of the mo... more The intrahippocampal injection of amyloid beta peptide (1–42) (Aβ(1–42)) represents one of the most useful animal models of Alzheimer disease. Since none of these available models fully represents the main pathological hallmarks of Alzheimer disease, stereotaxic Aβ(1–42) infusion provides researchers with an in vivo alternative paradigm. When performed by well-trained individuals, this model is the best-suited one for short-term studies focusing on the effects of Aβ(1–42) on a specific brain region or circuitry. Here, we describe all methodological phases of such a model.

Hippocampal organotypic cultures constitute a very easy but delicate method widely used to study ... more Hippocampal organotypic cultures constitute a very easy but delicate method widely used to study amyloid
β-peptide toxicity. This ex vivo technique is performed on tissues isolated from newborn rats. Here, we
describe a protocol for the preparation and culture of hippocampal organotypic slices that can be maintained
for 14–21 days and their application to the study of amyloid β-peptide toxicity.