Does neuroinflammation turn on the flame in Alzheimer's disease? Focus on astrocytes

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

Palmitoylethanolamide dampens reactive astrogliosis and improves neuronal trophic support in a triple transgenic model of Alzheimer’s disease: in vitro and in vivo evidence

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

Targeting neuroinflammation in Alzheimer’s disease

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

Psychiatric face of COVID-19

From Springer Nature via Jisc Publications RouterHistory: received 2020-06-02, rev-recd 2020-07-07, accepted 2020-07-14, registration 2020-07-22, pub-electronic 2020-07-30, online 2020-07-30, collection 2020-12Publication status: PublishedAbstract: The Coronavirus Disease 2019 (COVID-19) represents a severe multiorgan pathology which, besides cardio-respiratory manifestations, affects the function of the central nervous system (CNS). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similarly to other coronaviruses demonstrate neurotropism; the viral infection of the brain stem may complicate the course of the disease through damaging central cardio-respiratory control. The systemic inflammation as well as neuroinflammatory changes are associated with massive increase of the brain pro-inflammatory molecules, neuroglial reactivity, altered neurochemical landscape and pathological remodelling of neuronal networks. These organic changes, emerging in concert with environmental stress caused by experiences of intensive therapy wards, pandemic fears and social restrictions, promote neuropsychiatric pathologies including major depressive disorder, bipolar disorder (BD), various psychoses, obsessive-compulsive disorder and post-traumatic stress disorder. The neuropsychiatric sequelae of COVID-19 represent serious clinical challenge that has to be considered for future complex therapies

S100B inhibitor pentamidine attenuates reactive gliosis and reduces neuronal loss in a mouse model of Alzheimer's disease

Among the different signaling molecules released during reactive gliosis occurring in Alzheimer’s disease (AD), the astrocytederived S100B protein plays a key role in neuroinflammation, one of the hallmarks of the disease. The use of pharmacological tools targeting S100B may be crucial to embank its effects and some of the pathological features of AD. The antiprotozoal drug pentamidine is a good candidate since it directly blocks S100B activity by inhibiting its interaction with the tumor suppressor p53. We used a mouse model of amyloid beta- (A-) induced AD, which is characterized by reactive gliosis and neuroinflammation in the brain, and we evaluated the effect of pentamidine on the main S100B-mediated events. Pentamidine caused the reduction of glial fibrillary acidic protein, S100B, and RAGE protein expression, which are signs of reactive gliosis, and induced p53 expression in astrocytes. Pentamidine also reduced the expression of proinflammatory mediators and markers, thus reducing neuroinflammation in AD brain. In parallel, we observed a significant neuroprotection exerted by pentamidine on CA1 pyramidal neurons. We demonstrated that pentamidine inhibits A-induced gliosis and neuroinflammation in an animal model of AD, thus playing a role in slowing down the course of the disease

Application of Support Vector Machine on fMRI Data as Biomarkers in Schizophrenia Diagnosis: A Systematic Review

Non-invasive measurements of brain function and structure as neuroimaging in patients with mental illnesses are useful and powerful tools for studying discriminatory biomarkers. To date, functional MRI (fMRI), structural MRI (sMRI) represent the most used techniques to provide multiple perspectives on brain function, structure, and their connectivity. Recently, there has been rising attention in using machine-learning (ML) techniques, pattern recognition methods, applied to neuroimaging data to characterize disease-related alterations in brain structure and function and to identify phenotypes, for example, for translation into clinical and early diagnosis. Our aim was to provide a systematic review according to the PRISMA statement of Support Vector Machine (SVM) techniques in making diagnostic discrimination between SCZ patients from healthy controls using neuroimaging data from functional MRI as input. We included studies using SVM as ML techniques with patients diagnosed with Schizophrenia. From an initial sample of 660 papers, at the end of the screening process, 22 articles were selected, and included in our review. This technique can be a valid, inexpensive, and non-invasive support to recognize and detect patients at an early stage, compared to any currently available assessment or clinical diagnostic methods in order to save crucial time. The higher accuracy of SVM models and the new integrated methods of ML techniques could play a decisive role to detect patients with SCZ or other major psychiatric disorders in the early stages of the disease or to potentially determine their neuroimaging risk factors in the near future

Translational potential of astrocytes in brain disorders

Fundamentally, all brain disorders can be broadly defined as the homeostatic failure of this organ. As the brain is composed of many different cells types, including but not limited to neurons and glia, it is only logical that all the cell types/constituents could play a role in health and disease. Yet, for a long time the sole conceptualization of brain pathology was focused on the well-being of neurons. Here, we challenge this neuron-centric view and present neuroglia as a key element in neuropathology, a process that has a toll on astrocytes, which undergo complex morpho-functional changes that can in turn affect the course of the disorder. Such changes can be grossly identified as reactivity, atrophy with loss of function and pathological remodeling. We outline the pathogenic potential of astrocytes in variety of disorders, ranging from neurotrauma, infection, toxic damage, stroke, epilepsy, neurodevelopmental, neurodegenerative and psychiatric disorders, Alexander disease to neoplastic changes seen in gliomas. We hope that in near future we would witness glial-based translational medicine with generation of deliverables for the containment and cure of disorders. We point out that such as a task will require a holistic and multi-disciplinary approach that will take in consideration the concerted operation of all the cell types in the brain

Serotonergic modulation of rat pineal gland activity: In vivo evidence for a 5-hydroxytryptamine(2c) receptor involvement

There are some suggestions that, in the pineal gland, serotonin acts not only as a precursor of melatonin but also plays a role in the modulation of the pineal biosynthetic activity. To corroborate this possible neuromodulatory role of 5-hydroxytryptamine (serotonin) (5-HT) on the pineal gland, the effects of two 5-HT2 receptor agonists meta-chlorophenylpiperazine (m-CPP) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane were assessed in vivo on pineal N-acetyltransferase (NAT) activity and melatonin content in rats. m-CPP potentiated the enhancement of NAT activity and pineal melatonin content induced by isoproterenol administration during daytime, whereas it did not affect the diurnal basal biosynthetic activity of the gland. At night, m-CPP and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane enhanced significantly the physiological increases in both pineal NAT activity and melatonin content. This enhancement was prevented by pretreatment with N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride, an antagonist with higher affinity for 5-HT(2B/C) than for 5-HT(2A) receptor, as well as by pretreatment with 8-[5-(2,4-dimethoxy-5-(4-trifluoromethyl-phenylsulphonamido)-phenyl-5-oxopent hyl]-1,3,8-triazospiro[4,5]decane-2,4-dione, the most specific 5-HT(2C) receptor now available, but not by pretreatment with ketanserin, an antagonist with higher affinity for 5-HT(2A) than for 5-HT(2C) receptor. These results suggest that 5-HT(2C) receptors are likely involved in the mediation of the serotonergic modulation of pineal biosynthetic activity in rats

Neurotensin as Modulator of Basal Ganglia- Thalamocortical Motor Circuit – Emerging Evidence for Neurotensin NTS1 Receptor as a Potential Target in Parkinson\u27s Disease

This chapter is focused on the putative role of neurotensin in the development of Parkinson’s disease, a neurodegenerative disorder mainly characterized by a progressive loss of nigrostriatal dopaminergic neurons (Schimpff et al., 2001). Although a direct causal role of neurotensin in Parkinson’s disease has not yet clearly demonstrated, some convincing animal and human studies support the potential role of the peptide in the etiopathogenesis of this motor disorder. Special emphasis is placed on the significance that neurotensin plays on basal ganglia neuroplasticity and neurodegeneration. This is mainly supported by recent findings clearly demonstrating that neurotensin enhances glutamate excitotoxicity in mesencephalic dopamine neurons and that neurotensin receptors are involved in the modulation of NMDA-induced excitotoxicity (Antonelli et al., 2002; 2004). Through these mechanisms neurotensin could contribute to the development and/or the progression of neurodegenerative disorders. The possible use of neurotensin receptor antagonists, in combination with conventional therapy, in the treatment of Parkinson’s disease, is also discussed