Microglia and the Blood-Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions.

Microglia are the resident immune cells of the central nervous system that guarantee immune surveillance and exert also a modulating role on neuronal synaptic development and function. Upon injury, microglia get activated and modify their morphology acquiring an ameboid phenotype and pro- or anti-inflammatory features. The active role of microglia in blood-brain barrier (BBB) function and their interaction with different cellular components of the BBB-endothelial cells, astrocytes and pericytes-are described. Here, we report the specific crosstalk of microglia with all the BBB cell types focusing in particular on the involvement of microglia in the modulation of BBB function in neuroinflammatory conditions that occur in conjunction with an acute event, such as a stroke, or in a slow neurodegenerative disease, such as Alzheimer's disease. The potential of microglia to exert a dual role, either protective or detrimental, depending on disease stages and environmental conditioning factors is also discussed.

Microglia Contributes to BAF-312 Effects on Blood-Brain Barrier Stability.

Microglia, together with astrocytes and pericytes, cooperate to ensure blood-brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability. An in vitro BBB model was reproduced using human-derived endothelial cells, astrocytes and microglia. Co-cultures were exposed to inflammatory cytokines (TNFα, 10 UI and IFNγ, 5 UI) in the presence of BAF-312 (100 nM), and the BBB properties and microglia role were evaluated. The drug facilitated microglial migration towards endothelial/astrocyte co-cultures, involving the activity of the metalloprotease 2 (MMP2). Microglia actively cooperated with astrocytes in the maintenance of endothelial barrier stability: in the triple co-culture, selective treatment of microglial cells with BAF-312 significantly prevented cytokines' effects on the endothelial barrier. In conclusion, BAF-312, modulating S1P receptors in microglia, may contribute to the reinforcement of the endothelial barrier at the BBB, suggesting an additional effect of the drug in the treatment of multiple sclerosis.

Sphingosine-1-phosphate and Sphingosine-1-phosphate receptors in the cardiovascular system: pharmacology and clinical implications.

Sphingosine-1-phosphate (S1P) is a lipid that binds and activates five distinct receptor subtypes, S1P1, S1P2, S1P3, S1P4, S1P5, widely expressed in different cells, tissues and organs. In the cardiovascular system these receptors have been extensively studied, but no drug acting on them has been approved so far for treating cardiovascular diseases. In contrast, a number of S1P receptor agonists are approved as immunomodulators, mainly for multiple sclerosis, because of their action on lymphocyte trafficking. This chapter summarizes the available information on S1P receptors in the cardiovascular system and discusses their potential for treating cardiovascular conditions and/or their role on the clinical pharmacology of drugs so far approved for non-cardiovascular conditions. Basic research has recently produced data useful to understand the molecular pharmacology of S1P and S1P receptors, regarding biased agonism, S1P storage, release and vehiculation and chaperoning by lipoproteins, paracrine actions, intracellular non-receptorial S1P actions. On the other hand, the approval of fingolimod and newer generation S1P receptor ligands as immunomodulators, provides information on a number of clinical observations on the impact of these drugs on cardiovascular system which need to be integrated with preclinical data. S1P receptors are potential targets for prevention and treatment of major cardiovascular conditions, including hypertension, myocardial infarction, heart failure and stroke.

An In Vitro Model of the Blood-Brain Barrier to Study Alzheimer's Disease: The Role of ß-Amyloid and Its Influence on PBMC Infiltration.

The blood-brain barrier (BBB) is a highly specialized structure, constituted by endothelial cells that together with astrocytes and pericytes provide a functional interface between the central nervous system and the periphery. Several pathological conditions may affect its functions, and lately BBB involvement in the pathogenesis of Alzheimer's disease has been demonstrated. Both endothelial cells and astrocytes can be differentially affected during the course of the disease. In vitro BBB models present a powerful tool in evaluating the effects that ß-amyloid (Aß), or other pathogenic stimuli, play on the BBB at cellular level. In vitro BBB models derived from human cell sources are rare and not easily implemented. We generated two conditionally immortalized human cell lines, brain microvascular endothelial cells (TY10), and astrocytes (hAST), that, when co-cultured under appropriate conditions, exhibit BBB-like characteristics. This model allowed us to evaluate the transmigration of peripheral blood mononuclear cells (PBMCs) through the in vitro barrier exposed to Aß and the role played by astrocytes in the modulation of this phenomenon. We describe here the methodology used in our lab to set up our in vitro model of the BBB and to carry out a PBMC transmigration assay.

Microglial polarization differentially affects neuronal vulnerability to the ß-amyloid protein: Modulation by melatonin.

Microglial cells play a central but yet debated role in neuroinflammatory events occurring in Alzheimer's disease (AD). We here explored how microglial features are modulated by melatonin following ß-amyloid (Aß42)-induced activation and examined the cross-talk with Aß-challenged neuronal cells. Human microglial HMC3 cells were exposed to Aß42 (200 nM) in the presence of melatonin (MEL; 1 µM) added since the beginning (MELco) or after a 72 h-exposure to Aß42 (MELpost). In both conditions, MEL favored an anti-inflammatory activation and rescued SIRT1 and BDNF expression/release. Caspase-1 up-regulation and phospho-ERK induction following a prolonged exposure to Aß42 were prevented by MEL. In addition, MEL partially restored proteasome functionality that was altered by long-term Aß42 treatment, re-establishing both 20S and 26S chymotrypsin-like activity. Differentiated neuronal-like SH-SY5Y cells were exposed to Aß42 (200 nM for 24 h) in basal medium or in the presence of conditioned medium (CM) collected from microglia exposed for different times to Aß42 alone or in combination with MELco or MELpost. Aß42 significantly reduced pre-synaptic proteins synaptophysin and VAMP2 and mean neuritic length. These effects were prevented by CM from anti-inflammatory microglia (Aß42 for 6 h), or from MELco and MELpost microglia, but the reduction of neuritic length was not rescued when the SIRT1 inhibitor EX527 was added. In conclusion, our data add to the concept that melatonin shows a promising anti-inflammatory action on microglia that is retained even after pro-inflammatory activation, involving modulation of proteasome function and translating into neuroprotective microglial effects.

CNS-Sparing Histamine H3 Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms.

Among the histamine receptors, growing evidence points to the histamine H3 receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H3 receptor antagonist, on the autonomic neuropathy of the intestinal tract associated with diabetes. Diabetes was induced in male BALB/c mice by a single high dose of streptozotocin (150 mg/kg). Colorectal specimens from control and diabetic mice, randomized to vehicle or PF0086087 (10, 30, 100 mg/kg/day by oral gavage for 14 days), were processed for morphological and immunohistochemical analysis. A significant overproduction of mucus in the intestinal mucosa of diabetic mice compared to the controls was observed. PF0086087 at the highest dose prevented mucin overproduction. The immunohistochemistry analysis demonstrated that diabetes causes a decrease in the inhibitory component of enteric motility, measured as the percentage of neuronal nitric oxide synthase-positive neurons (p < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (p < 0.01). PF0086087 dose-dependently prevented these pathophysiological events. In conclusion, PF0086087 may be an essential tool in preventing nitrergic dysfunction in the myenteric plexus of the distal colon and diabetes-induced gastrointestinal complications.

Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease: The Need for a Holistic View of the Early Pathogenesis.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, a socio-economic burden destined to worsen with increased population aging [...].

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aß: An Early but Transient Response Rescued by Melatonin.

Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer's disease (AD), a pro-inflammatory switch may occur, leading to loss of protective functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of ß-amyloid peptide 1-42 (Aß42; 0.2 µM) initially (6 h) upregulated anti-inflammatory markers interleukin (IL)-4, IL-13, and brain-derived neurotrophic factor (BDNF). BDNF increase was prevented by selective inhibition of SIRT1 with EX527 (2 µM). Accordingly, these early effects were accompanied by a significant Aß42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aß42, while the AMPK inhibitor BML-275 (2 µM) attenuated Aß42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aß42 was prolonged (0.2 µM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1ß and tumor necrosis factor (TNF)-α increased. This coincided with a rise in NF-kB nuclear localization. The effects of melatonin (1 µM) on prolonged microglial exposure to Aß42 were analyzed for their protective potential. Melatonin was able to prolong SIRT1 and BDNF upregulation, as well as to prevent NF-kB nuclear translocation and acetylation. These effects were sensitive to the melatonin receptor antagonist, luzindole (25 µM). In conclusion, our data define an early microglial defensive response to Aß42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection.

Protective effect of the sphingosine-1 phosphate receptor agonist siponimod on disrupted blood brain barrier function.

Sphingosine 1 phosphate (S1P) is a bioactive sphingolipid that exerts several functions in physiological and pathological conditions. The modulation of one of its receptors, S1P1, plays an important role in the egress of lymphocytes from lymph nodes and is a useful target in multiple sclerosis (MS) treatment. A new drug, siponimod (BAF-312) has been recently approved for the treatment of secondary progressive MS and has affinity for two S1P receptors, S1P1 and S1P5. The two receptors are expressed by endothelial cells that, as components of the blood-brain barrier (BBB), prevent the access of solutes and lymphocytes into the central nervous system, function often compromised in MS. Using an in vitro BBB model exposed to inflammatory cytokines (TNFα and IFNγ, 5 UI and 10 UI respectively), we evaluated the effects of BAF-312 (100 nM) on expression and function of endothelial tight junctional proteins (Zo-1 and claudin-5), regulation of transendothelial electrical resistance (TEER) and permeability to FITC-conjugated dextran. Zo-1 expression, as well as TEER values, were promptly recovered (24 h) when both S1P1 and S1P5 were activated by BAF-312. In contrast, at this time point, activation of S1P5 with the selective agonist UC-42-WP04 (300 nM) or with BAF-312, under blockade of S1P1 with the selective antagonist NIBR-0213 (1 µM), resulted in recovery of expression and localization of claudin-5 and reduction of TNFα/INFγ-induced expression of metalloproteinase 9. Only after a prolonged BAF-312 exposure (48 h), S1P1 was involved through activation of the PI3K/Akt pathway. The PI3K inhibitor LY294002 (10 µM) prevented in fact the effects of BAF-312 on all the parameters examined. In conclusion, BAF-312, by modulating both S1P1 and S1P5, may strengthen BBB properties, thus providing additional effects in the treatment of MS.

Reciprocal Interplay Between Astrocytes and CD4+ Cells Affects Blood-Brain Barrier and Neuronal Function in Response to ß Amyloid.

Background: In Alzheimer's disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. However, the role of T cells, once they migrate into the CNS, is not well defined. CD4+ cells interact with astrocytes able to release several factors and cytokines that can modulate T cell polarization; similarly, astrocytic properties are modulated after interaction with T cells. Methods: In in vitro models, astrocytes were primed with ß-amyloid (Aß; 2.5 µM, 5 h) and then co-cultured with magnetically isolated CD4+ cells. Cytokines expression was evaluated both in co-cultured CD4+ cells and astrocytes. The effects of this crosstalk were further evaluated by co-culturing CD4+ cells with the neuronal-like SH-SY5Y cell line and astrocytes with endothelial cells. Results: The pattern of cytokines and trophic factors expressed by CD4+ cells were strongly modulated in the presence of Aß-primed astrocytes. Specifically, the percentage of IL-4+ and IFNγ+ CD4+ cells was significantly increased and reduced, respectively. Further, increased BDNF mRNA levels were observed in CD4+ cells. When SH-SY5Y cells were co-cultured with astrocyte-conditioned CD4+ cells and exposed to Aß, the reduction of the presynaptic protein synaptophysin was prevented with a BDNF-dependent mechanism. In astrocytes co-cultured with CD4+ cells, reduced mRNA levels of inflammatory cytokines and VEGF were observed. This was paralleled by the prevention of the reduction of claudin-5 when astrocytes were co-cultured with endothelial cells. Conclusion: Following Aß exposure, there exists reciprocal crosstalk between infiltrating peripheral cells and astrocytes that in turn affects not only endothelial function and thus BBB properties, but also neuronal behavior. Since astrocytes are the first cells that lymphocytes interact with and are among the principal players in neuroinflammation occurring in AD, understanding this crosstalk may disclose new potential targets of intervention in the treatment of neurodegeneration.

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs.

Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.

SIRT1 Mediates Melatonin's Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence.

Melatonin exerts direct neuroprotection against cerebral hypoxic damage, but the mechanisms of its action on microglia have been less characterized. Using both in vitro and in vivo models of hypoxia, we here focused on the role played by silent mating type information regulation 2 homolog 1 (SIRT1) in melatonin's effects on microglia. Viability of rat primary microglia or microglial BV2 cells and SH-SY5Y neurons was significantly reduced after chemical hypoxia with CoCl2 (250 µM for 24 h). Melatonin (1 µM) significantly attenuated CoCl2 toxicity on microglia, an effect prevented by selective SIRT1 inhibitor EX527 (5 µM) and AMP-activated protein kinase (AMPK) inhibitor BML-275 (2 µM). CoCl2 did not modify SIRT1 expression, but prevented nuclear localization, while melatonin appeared to restore it. CoCl2 induced nuclear localization of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-kB), an effect contrasted by melatonin in an EX527-dependent fashion. Treatment of microglia with melatonin attenuated potentiation of neurotoxicity. Common carotid occlusion was performed in p7 rats, followed by intraperitoneal injection of melatonin (10 mg/kg). After 24 h, the number of Iba1+ microglia in the hippocampus of hypoxic rats was significantly increased, an effect not prevented by melatonin. At this time, SIRT1 was only detectable in the amoeboid, Iba1+ microglial population selectively localized in the corpus callosum. In these cells, nuclear localization of SIRT1 was significantly lower in hypoxic animals, an effect prevented by melatonin. NF-kB showed an opposite expression pattern, where nuclear localization in Iba1+ cells was significantly higher in hypoxic, but not in melatonin-treated animals. Our findings provide new evidence for a direct effect of melatonin on hypoxic microglia through SIRT1, which appears as a potential pharmacological target against hypoxic-derived neuronal damage.

The Ambiguous Role of Microglia in Aß Toxicity: Chances for Therapeutic Intervention.

Amyloid-ß (Aß) has long been shown to be critical in Alzheimer's disease pathophysiology. Microglia contributes to the earliest responses to Aß buildup, by direct interaction through multiple receptors. Microglial cells operate Aß clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance. But in time and with aging, the fine balance between pro- and anti-inflammatory activity of microglia deranges, negatively impacting its Aß-clearing ability. Furthermore, in recent years, microglial activation has proven to be much more complex than the mere dichotomic pro/antiinflammatory polarization previously accepted. Microglia can display a wide spectrum of phenotypes, which can even be mixed. On these bases, it is evident that while pharmacological intervention aiding microglia to prolong its ability to cope with Aß buildup could be extremely relevant, its feasibility is hampered by such high complexity, which still needs to be completely understood.

Astrocyte-Derived Paracrine Signals: Relevance for Neurogenic Niche Regulation and Blood-Brain Barrier Integrity.

Astrocytes are essential for proper regulation of the central nervous system (CNS). Importantly, these cells are highly secretory in nature. Indeed they can release hundreds of molecules which play pivotal physiological roles in nervous tissues and whose abnormal regulation has been associated with several CNS disorders. In agreement with these findings, recent studies have provided exciting insights into the key contribution of astrocyte-derived signals in the pleiotropic functions of these cells in brain health and diseases. In the future, deeper analysis of the astrocyte secretome is likely to further increase our current knowledge on the full potential of these cells and their secreted molecules not only as active participants in pathophysiological events, but as pharmacological targets or even as therapeutics for neurological and psychiatric diseases. Herein we will highlight recent findings in our and other laboratories on selected molecules that are actively secreted by astrocytes and contribute in two distinct functions with pathophysiological relevance for the astroglial population: i) regulation of neural stem cells (NSCs) and their progeny within adult neurogenic niches; ii) modulation of the blood-brain barrier (BBB) integrity and function.

Astrocytes Modify Migration of PBMCs Induced by ß-Amyloid in a Blood-Brain Barrier in vitro Model.

BACKGROUND: The brain is protected by the blood-brain barrier (BBB), constituted by endothelial cells supported by pericytes and astrocytes. In Alzheimer's disease a dysregulation of the BBB occurs since the early phases of the disease leading to an increased access of solutes and immune cells that can participate to the central inflammatory response. Here we investigated whether astrocytes may influence endothelial-leukocytes interaction in the presence of amyloid-ß (Aß). METHODS: We used an in vitro BBB model, where endothelial cells, cultured alone or with astrocytes were exposed for 5 h to Aß, both under resting or inflammatory conditions (TNFα and IFNγ), to evaluate endothelial barrier properties, as well as transendothelial migration of peripheral blood mononuclear cells (PBMCs). RESULTS: In the co-culture model, barrier permeability to solutes was increased by all treatments, but migration was only observed in inflammatory conditions and was prevented by Aß treatment. On the contrary, in endothelial monocultures, Aß induced leukocytes migration under resting conditions and did not modify that induced by inflammatory cytokines. In endothelial astrocyte co-cultures, a low molecular weight (MW) isoform of the adhesion molecule ICAM-1, important to allow interaction with PBMCs, was increased after 5 h exposure to inflammatory cytokines, an effect that was prevented by Aß. This modulation by Aß was not observed in endothelial monocultures. In addition, endothelial expression of ß-1,4-N-acetylglucosaminyltransferase III (Gnt-III), responsible for the formation of the low MW ICAM-1 isoform, was enhanced in inflammatory conditions, but negatively modulated by Aß only in the co-culture model. miR-200b, increased in astrocytes following Aß treatment and may represent one of the factors involved in the control of Gnt-III expression. CONCLUSION: These data point out that, at least in the early phases of Aß exposure, astrocytes play a role in the modulation of leukocytes migration through the endothelial layer.

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

Alzheimer's disease (AD) is characterized by extensive neurodegeneration and inflammation in selective brain areas, linked to severely disabling cognitive deficits. Before full manifestation, different stages appear with progressively increased brain pathology and cognitive impairment. This significantly extends the time lag between initial molecular triggers and appearance of detectable symptoms. Notably, a number of studies in the last decade have revealed that in the early stage of mild cognitive impairment, events that appear in contrast with neuronal distress may occur. These have been reproduced in vitro and in animal models and include increase in synaptic elements, increase in synaptic and metabolic activity, enhancement of neurotrophic milieu and changes in glial cell reactivity and inflammation. They have been interpreted as compensatory responses that could either delay disease progression or, in the long run, result detrimental. For this reason, these mechanisms define a new and previously undervalued window of opportunity for intervention. Their importance resides especially in their early appearance. Directing efforts to better characterize this stage, in order to identify new pharmacological targets, is an exciting new avenue to future advances in AD research.

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders.

The contribution of microglia to early synaptic compensatory responses that precede ß-amyloid-induced neuronal death.

Glial-neuronal cross-talk has a critical role in the development of neurodegenerative conditions, including Alzheimer's Disease, where it affects neuronal responses to ß-amyloid peptide (Aß)-induced toxicity. We set out to identify factors regulating synaptic responses to Aß, dissecting the specific role of glial signaling. A low concentration of aggregated Aß42 induced selective up-regulation of mature brain-derived neurotrophic factor (BDNF) expression and release in rat organotypic hippocampal cultures as well as in cortical pure microglia. Conditioned media from resting (CMC) or Aß42-treated (CMA) microglia were tested for their effects on synaptophysin expression in SH-SY5Y neuronal-like cells during challenge with Aß42. Both CMC and CMA prevented Aß-induced synaptophysin loss. In the presence of Aß + CMA, synaptophysin was over-expressed, although it appeared partly clumped in cell bodies. Synaptophysin over-expression was not directly dependent on BDNF signaling on neuronal-like cells, but relied on autocrine BDNF action on microglia. FM1-43 labeling experiments revealed compromised synaptic vesicle recycling in Aß42-treated neuronal-like cells, rescued by microglial conditioned medium. In these conditions, significant and prolonged neuroprotection was observed. Our results point to microglia as a target for early intervention, given its positive role in supporting neuronal compensatory responses to Aß synaptotoxicity, which potentially lead to their extended survival.

Neurobiological links between depression and AD: The role of TGF-ß1 signaling as a new pharmacological target.

In the last several years a large number of studies have demonstrated the neurobiological and clinical continuum between depression and Alzheimer's disease (AD). Depression is a risk factor for the development of AD, and the presence of depressive symptoms significantly increases the conversion of Mild Cognitive Impairment (MCI) into AD. Common pathophysiological events have been identified in depression and AD, including neuroinflammation with an aberrant Tumor Necrosis Factor-α (TNF-α) signaling, and an impairment of Brain-Derived Neurotrophic Factor (BDNF) and Transforming-Growth-Factor-ß1 (TGF-ß1) signaling. TGF-ß1 is an anti-inflammatory cytokine that exerts neuroprotective effects against amyloid-ß (Aß)-induced neurodegeneration, and it has a key role in memory formation and synaptic plasticity. TGF-ß1 plasma levels are reduced in major depressed patients (MDD), correlate with depression severity, and significantly contribute to treatment resistance in MDD. The deficit of Smad-dependent TGF-ß1 signaling is also an early event in AD pathogenesis, which contributes to inflammaging and cognitive decline in AD. A long-term treatment with antidepressants such as selective-serotonin-reuptake inhibitors (SSRIs) is known to reduce the risk of AD in patients with depression and, SSRIs, such as fluoxetine, increase the release of TGF-ß1 from astrocytes and exert relevant neuroprotective effects in experimental models of AD. We propose the TGF-ß1 signaling pathway as a common pharmacological target in depression and AD, and discuss the potential rescue of TGF-ß1 signaling by antidepressants as a way to prevent the transition from depression to AD.

Estrogen and Alzheimer's disease: Still an attractive topic despite disappointment from early clinical results.

Since publication of the results of the Women Health Initiative Memory Study demonstrating that hormone therapy initiated late after menopause increases the risk of dementia in women, attempts have been made to identify a "critical window of intervention". In the meantime, basic research carried out in the last 10-15 years has reinforced the concept of a strong impact of estrogen in neuroprotection, moving also into novel directions that include characterization of estrogen's effect on non-neuronal cells, mitochondrial function, miRNA production and novel targets for their action in the central nervous system (CNS). All these findings, together with a list of recent animal models of Alzheimer's Disease that appear feasible for the study of estrogen's CNS effect are here summarized and accompanied by the most recent data from clinical trials in which hormone therapy was initiated early after menopause.