Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets.

Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes' transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.

Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways.

Several epidemiological studies show an inverse association between cancer and Alzheimer's disease (AD). It is debated whether this association is the consequence of biological mechanisms shared by both these conditions or may be related to the pharmacological treatments carried out on the patients. The latter hypothesis, however, is not sustained by the available evidence. Hence, the focus of this review is to analyze common biological mechanisms for both cancer and AD and to build up a biological theory useful to explain the inverse correlation between AD and cancer. The review proposes a hypothesis, according to which several molecular players, prominently PIN1 and p53, have been investigated and considered involved in complex molecular interactions putatively associated with the inverse correlation. On the other hand, p53 involvement in both diseases seems to be a consequence of the aberrant activation of other proteins. Instead, PIN1 may be identified as a novel key regulator at the crossroad between cancer and AD. PIN1 is a peptidyl-prolyl cis-trans isomerase that catalyzes the cis-trans isomerization, thus regulating the conformation of different protein substrates after phosphorylation and modulating protein function. In particular, trans-conformations of Amyloid Precursor Protein (APP) and tau are functional and "healthy", while cis-conformations, triggered after phosphorylation, are pathogenic. As an example, PIN1 accelerates APP cis-to-trans isomerization thus favoring the non-amyloidogenic pathway, while, in the absence of PIN1, APP is processed through the amyloidogenic pathway, thus predisposing to neurodegeneration. Furthermore, a link between PIN1 and tau regulation has been found, since when PIN1 function is inhibited, tau is hyperphosphorylated. Data from brain specimens of subjects affected by mild cognitive impairment and AD have revealed a very low PIN1 expression. Moreover, polymorphisms in PIN1 promoter correlated with an increased PIN1 expression are associated with a delay of sporadic AD age of onset, while a polymorphism related to a reduced PIN1 expression is associated with a decreased risk of multiple cancers. In the case of dementias, in particular of Alzheimer's disease, new biological markers and targets based on the discussed players can be developed based on a theoretical approach relying on different grounds compared to the past. An unbiased expansion of the rationale and of the targets may help to achieve in the field of neurodegenerative dementias similar advances to those attained in the case of cancer treatment.

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation.

An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation.

Beta-amyloid short- and long-term synaptic entanglement.

Beta-amyloid (Aß) is a peptide that derives from the proteolytic cleavage of the amyloid precursor protein (APP) by several secretases. Since its isolation and sequencing from Alzheimer's disease (AD) brains, Aß has been intensively investigated in the context of AD as the main pathogenic marker responsible for neurodegenerative processes. During the last three decades, results from several independent studies have converged to form the so-called amyloid cascade hypothesis of AD and several therapeutic strategies designed to modulate the APP amyloidogenic pathway have been developed. However, none of the clinical trials targeting Aß culminated in a significant clinical outcome, thus challenging the concept that targeting Aß, at least within the time window so far explored in clinical trials, may have a therapeutic effect. However, besides its presence in AD brains, brain cells produce Aß, thus suggesting that, under normal conditions, the peptide may have a role in the regulation of brain functions, which is consistent with its ubiquitous presence and normal synthesis. Taking into account that Aß has been found to exhibit a dual role strictly correlated with its concentration (neuromodulatory/neuroprotective vs neurotoxic), we discuss emerging evidence indicating that physiological concentrations of Aß peptide modulate synaptic activity. The review examines the physiological effects of Aß on acute synaptic activities and the functional interplay existing between Aß and different neurotransmitter systems, i.e. cholinergic, glutamatergic, GABAergic, catecholaminergic, serotoninergic, and peptidergic. The review also provides an insight into the different mechanisms through which Aß affects synaptic activity, focusing in particular on Aß interaction with the key synaptic proteins that regulate the neurotransmitter release machinery. These interactions may help to identify or recognize alterations in neurotransmitter activity and correlated behaviors as predictive signs for the development of AD and to understand the limitations of current interventions and the failure so far of amyloid targeted therapies.

Dual-Functioning Scaffolds for the Treatment of Spinal Cord Injury: Alginate Nanofibers Loaded with the Sigma 1 Receptor (S1R) Agonist RC-33 in Chitosan Films.

The present work proposed a novel therapeutic platform with both neuroprotective and neuroregenerative potential to be used in the treatment of spinal cord injury (SCI). A dual-functioning scaffold for the delivery of the neuroprotective S1R agonist, RC-33, to be locally implanted at the site of SCI, was developed. RC-33-loaded fibers, containing alginate (ALG) and a mixture of two different grades of poly(ethylene oxide) (PEO), were prepared by electrospinning. After ionotropic cross-linking, fibers were incorporated in chitosan (CS) films to obtain a drug delivery system more flexible, easier to handle, and characterized by a controlled degradation rate. Dialysis equilibrium studies demonstrated that ALG was able to form an interaction product with the cationic RC-33 and to control RC-33 release in the physiological medium. Fibers loaded with RC-33 at the concentration corresponding to 10% of ALG maximum binding capacity were incorporated in films based on CS at two different molecular weights-low (CSL) and medium (CSM)-solubilized in acetic (AA) or glutamic (GA) acid. CSL- based scaffolds were subjected to a degradation test in order to investigate if the different CSL salification could affect the film behavior when in contact with media that mimic SCI environment. CSL AA exhibited a slower biodegradation and a good compatibility towards human neuroblastoma cell line.

Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea.

The immune system is an efficient integrated network of cellular elements and chemicals developed to preserve the integrity of the organism against external insults and its correct functioning and balance are essential to avoid the occurrence of a great variety of disorders. To date, evidence from literature highlights an increase in immunological diseases and a great attention has been focused on the development of molecules able to modulate the immune response. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of herbal medicines as integrative, complementary and preventive therapy. The active components in medical plants have always been an important source of clinical therapeutics and the study of their molecular pharmacology is an enormous challenge since they offer a great chemical diversity with often multi-pharmacological activity. In this review, we mainly analysed the immunomodulatory/antinflammatory activity of Echinacea spp. and Curcuma longa, focusing on some issues of the phytochemical research and on new possible strategies to obtain novel agents to supplement the present therapies.

Curcumin in Alzheimer's disease: Can we think to new strategies and perspectives for this molecule?

Population aging is an irreversible global trend with economic and socio-political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer's disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer's brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy.

Role of spliceosome proteins in the regulation of glucocorticoid receptor isoforms by cortisol and dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA) can counteract the activity of cortisol by modulating the glucocorticoid receptor ß (GRß) expression and antagonizing the binding of GRα to the glucocorticoid responsive element (GRE) in RACK1 (Receptor for Activated C Kinase 1) promoter. These observations are important in the context of immunosenescence and can be extended to recognize a complex hormonal balance in the control of GR isoform expression and consequently in the expression of GR responsive genes. To elucidate the mechanism of DHEA on GR alternative splicing, we investigated its possible involvement in the expression of proteins such as the Serine/arginine (SR)-Rich Splicing Factors (SRSF) regulating GR splicing, specifically SRSF9 and SRSF3 also known as SRp30c and SRp20 respectively. We demonstrated that DHEA can induce the up-regulation of GR mRNA which is preferentially directed toward the ß isoform. The effect is due to an increase in expression of the splicing factor SRSF9. On the other hand cortisol up-regulated SRSF3, the splicing factor promoting GRα isoform. We demonstrated that DHEA and cortisol modulate SRSF9 and SRSF3 in a different way and our data suggest that the anti-glucocorticoid effect of DHEA, among other mechanisms, is also exerted by modulating the expression of proteins involved in the splicing of the GR pre-mRNA.

Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence.

Immunosenescence defines the decline in immune function that occurs with aging. This has been associated, at least in part, with defective cellular signaling via protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC activation and consequently reduced response to lipopolysaccharide (LPS) stimulation and cytokine release. The lack of PKC activation seems to be dependent on the reduced expression of the receptor for activated C kinase 1 (RACK1), a scaffolding protein involved in multiple signal transduction cascades. The defective expression of RACK1 may be dependent on age-related alteration of the balance between the adrenal hormones cortisol and dehydroepiandrosterone (DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These hormonal changes are significant in the context of RACK1 expression and signaling function because DHEA administration in vivo and in vitro can restore the levels of RACK1 and the function of the PKC signaling cascade in aged animals and in human cells. In contrast, there is evidence that cortisol can act as a negative transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a glucocorticoid responsive element that is also involved in androgen signaling. Furthermore DHEA may have an indirect influence on the post-transcriptional regulation of the functions of the glucocorticoid receptor. In this review, we will examine the role of the hormonal regulation of rack1 gene transcriptional regulation and the consequences on signaling and function in immune cells and immunosenescence.

Do we need pharmacogenetics to personalize antidepressant therapy?

This review examines the role of drug metabolism and drug target polymorphism in determining the clinical response to antidepressants. Even though antidepressants are the most effective available treatment for depressive disorders, there is still substantial need for improvement due to the slow onset of appreciable clinical improvement and the association with side effects. Moreover, a substantial group of patients receiving antidepressant therapy does not achieve remission or fails to respond entirely. Even if the large variation in antidepressant treatment outcome across individuals remains poorly understood, one possible source of this variation in treatment outcome are genetic differences. The review focuses on a few polymorphisms which have been extensively studied, while reporting a more comprehensive reference to the existing literature in table format. It is relatively easy to predict the effect of polymorphisms in drug metabolizing enzymes, such as cytochromes P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19), which may be determined in the clinical context in order to explain or prevent serious adverse effects. The role of target polymorphism, however, is much more difficult to establish and may be more relevant for disease susceptibility and presentation rather than for response to therapy.

Zyxin is a novel target for ß-amyloid peptide: characterization of its role in Alzheimer's pathogenesis.

Zyxin is an adaptor protein recently identified as a novel regulator of the homeodomain-interacting protein kinase 2 (HIPK2)-p53 signaling in response to DNA damage. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer 's disease (AD), because of a deregulation of HIPK2 activity, leading to an impaired and dysfunctional response to stressors. Here, we examined the molecular mechanisms underlying the deregulation of HIPK2 activity in two cellular models, HEK-293 cells and SH-SY5Y neuroblastoma cells differentiated with retinoic acid over-expressing the amyloid precursor protein, focusing on the evidence that zyxin expression is important to maintain HIPK2 protein stability. We demonstrated that both beta-amyloid (Aß) 1-40 and 1-42 induce zyxin deregulation, thus affecting the transcriptional repressor activity of HIPK2 onto its target promoter, metallothionein 2A, which is in turn responsible for the induction of an altered conformational state of p53. We demonstrate for the first time that zyxin is a novel target of Aß activities in AD. These results may help the studies on the pathogenesis of AD, through the fine dissection of events related to beta-amyloid activities.

The Fuzzy Border between the Functional and Dysfunctional Effects of Beta-Amyloid: A Synaptocentric View of Neuron-Glia Entanglement.

Recent observations from clinical trials using monoclonal antibodies against Aß seem to suggest that Aß-targeting is modestly effective and not sufficiently based on an effective challenge of the role of Aß from physiological to pathological. After an accelerated approval procedure for aducanumab, and more recently lecanemab, their efficacy and safety remain to be fully defined despite previous attempts with various monoclonal antibodies, and both academic institutions and pharmaceutical companies are actively searching for novel treatments. Aß needs to be clarified further in a more complicated context, taking into account both its accumulation and its biological functions during the course of the disease. In this review, we discuss the border between activities affecting early, potentially reversible dysfunctions of the synapse and events trespassing the threshold of inflammatory, self-sustaining glial activation, leading to irreversible damage. We detail a clear understanding of the biological mechanisms underlying the derangement from function to dysfunction and the switch of the of Aß role from physiological to pathological. A picture is emerging where the optimal therapeutic strategy against AD should involve a number of allied molecular processes, displaying efficacy not only in reducing the well-known AD pathogenesis players, such as Aß or neuroinflammation, but also in preventing their adverse effects.

Nuclear factor κB-dependent neurite remodeling is mediated by Notch pathway.

In this study, we evaluated whether a cross talk between nuclear factor κB (NF-κB) and Notch may take place and contribute to regulate cell morphology and/or neuronal network in primary cortical neurons. We found that lack of p50, either induced acutely by inhibiting p50 nuclear translocation or genetically in p50(-/-) mice, results in cortical neurons characterized by reduced neurite branching, loss of varicosities, and Notch1 signaling hyperactivation. The neuronal morphological effects found in p50(-/-) cortical cells were reversed after treatment with the γ-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-1-alanyl 1]-S-phenylglycine t-butyl ester) or Notch RNA interference. Together, these data suggested that morphological abnormalities in p50(-/-) cortical neurons were dependent on Notch pathway hyperactivation, with Notch ligand Jagged1 being a major player in mediating such effect. In this line, we demonstrated that the p50 subunit acts as transcriptional repressor of Jagged1. We also found altered distribution of Notch1 and Jagged1 immunoreactivity in the cortex of p50(-/-) mice compared with wild-type littermates at postnatal day 1. These data suggest the relevance of future studies on the role of Notch/NF-κB cross talk in regulating cortex structural plasticity in physiological and pathological conditions.

The Frailty Puzzle: Searching for Immortality or for Knowledge Survival?

What is the value of assessing the biological age and frailty and predicting residual lifespan and health status? The benefit is obvious if we have means to alter the pace of aging and the development of frailty. So far, limited but increasing examples of interventions altering the predicted status indicate that, at least in some cases, this is possible through interventions spanning from the economic-social through drug treatments. Thus, why searching for biological markers, when some clinical and socio-economic indicators do already provide sufficiently accurate predictions? Indeed, the search of frailty biomarkers and of their biological clocks helps to build up a mechanistic frame that may orientate the design of interventions and the time window of their efficacy. Among the candidate biomarkers identified, several studies converge to indicate epigenetic clocks as a promising sensitive biomarker of the aging process. Moreover, it will help to establish the relationship between personal aging and health trajectories and to individuate the check points beyond which biological changes are irreversible.

The Circadian Molecular Machinery in CNS Cells: A Fine Tuner of Neuronal and Glial Activity With Space/Time Resolution.

The circadian molecular machinery is a fine timekeeper with the capacity to harmonize physiological and behavioral processes with the external environment. This tight-knit regulation is coordinated by multiple cellular clocks across the body. In this review, we focus our attention on the molecular mechanisms regulated by the clock in different brain areas and within different cells of the central nervous system. Further, we discuss evidence regarding the role of circadian rhythms in the regulation of neuronal activity and neurotransmitter systems. Not only neurons, but also astrocytes and microglia actively participate in the maintenance of timekeeping within the brain, and the diffusion of circadian information among these cells is fine-tuned by neurotransmitters (e.g., dopamine, serotonin, and γ-aminobutyric acid), thus impacting on the core clock machinery. The bidirectional interplay between neurotransmitters and the circadian clockwork is fundamental in maintaining accuracy and precision in daily timekeeping throughout different brain areas. Deepening the knowledge of these correlations allows us to define the basis of drug interventions to restore circadian rhythms, as well as to predict the onset of drug treatment/side effects that might promote daily desynchronization. Furthermore, it may lead to a deeper understanding of the potential impacts of modulations in rhythmic activities on the pace of aging and provide an insight in to the pathogenesis of psychiatric diseases and neurodegenerative disorders.

Molecular regulations of circadian rhythm and implications for physiology and diseases.

The term "circadian rhythms" describes endogenous oscillations with ca. 24-h period associated with the earth's daily rotation and light/dark cycle. Such rhythms reflect the existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt the internal environment with the external cues. At the molecular level, the circadian clock consists of multiple sets of transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, in addition to their primary role as generator of circadian rhythm, the biological clock plays a key role in controlling physiological functions of almost all tissues and organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair and response, angiogenesis, metabolic and redox homeostasis, to inflammatory and immune response. In this review, we summarize findings showing the crosstalk between the circadian molecular clock and some key intracellular pathways, describing a scenario wherein their reciprocal regulation impinges upon several aspects of mammalian physiology. Moreover, based on evidence indicating that circadian rhythms can be challenged by environmental factors, social behaviors, as well as pre-existing pathological conditions, we discuss implications of circadian misalignment in human pathologies, such as cancer and inflammatory diseases. Accordingly, disruption of circadian rhythm has been reported to affect several physiological processes that are relevant to human diseases. Expanding our understanding of this field represents an intriguing and transversal medicine challenge in order to establish a circadian precision medicine.

Inhibition of ß-Amyloid Aggregation in Alzheimer's Disease: The Key Role of (Pro)electrophilic Warheads.

Catechols have been largely investigated as antiaggregating agents toward ß-amyloid peptide. Herein, as a follow up of a previous series of hydroxycinnamic derivatives, we synthesized a small set of dihydroxy isomers for exploring the role of the reciprocal position of the two hydroxyl functions at a molecular level. Para- and ortho-derivatives effectively reduced amyloid fibrillization, while the meta-analogue was devoid of any activity in this respect. Electrochemical analyses showed that the antiaggregating potency correlates with the oxidation potential, hence indicating the proelectrophilic character as a prerequisite for activity. Interestingly, mass spectrometry studies and quantum mechanical calculations revealed different modes of action for active para- and ortho-derivatives, involving covalent or noncovalent interactions with ß-amyloid. The distinctive mode of action is also translated into a different cytotoxicity profile. This work clearly shows how apparently minimal structural modifications can completely change the compound behavior and generate alternative mechanisms of action of proelectrophilic chemical probes.

(Dys)regulation of Synaptic Activity and Neurotransmitter Release by ß-Amyloid: A Look Beyond Alzheimer's Disease Pathogenesis.

Beside its widely studied role in the pathogenesis of Alzheimer's disease (AD), ß-amyloid (Aß) is a normal and soluble product of neuronal metabolism that regulates several key physiological functions, exerting neuromodulatory effects on synaptic plasticity, memory, and neurotransmitter release. Such effects have been observed to occur in a hormetic fashion, with Aß exhibiting a dual role influenced by its concentration, the different isoforms, or aggregation forms of the peptide. However, to date, our knowledge about the physiological functions of Aß and, in particular, its modulatory role on synaptic activity and neurotransmission in the normal brain is fragmentary, thus hindering a clear comprehension of the biological mechanisms underlying the derangement from function to dysfunction. In particular, according to the amyloid cascade hypothesis, the switch from physiology to pathology is linked to the abnormal increase in Aß levels, due to an imbalance in Aß production and clearance. In this regard, increased Aß levels have been hypothesized to induce early defects in synaptic function and such alterations have been suggested to account, at least in part, for the onset of neuropsychiatric symptoms (e.g., apathy, anxiety, changes in mood, depression, and agitation/aggression), frequently observed in the prodromal stage of AD. Therefore, understanding the biological mechanisms underlying early synaptic alterations in AD is a key starting point to frame the relevant time windows for AD treatment and to gain insight into AD etiopathogenesis.

The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration.

The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts. While its implication in proliferating cells, and, in particular, in the field of cancer, has been widely characterized, less is known about Pin1 biological functions in terminally differentiated and post-mitotic neurons. Notably, Pin1 is widely expressed in the central and peripheral nervous system, where it regulates a variety of neuronal processes, including neuronal development, apoptosis, and synaptic activity. However, despite studies reporting the interaction of Pin1 with neuronal substrates or its involvement in specific signaling pathways, a more comprehensive understanding of its biological functions at neuronal level is still lacking. Besides its implication in physiological processes, a growing body of evidence suggests the crucial involvement of Pin1 in aging and age-related and neurodegenerative diseases, including Alzheimer's disease, Parkinson disease, frontotemporal dementias, Huntington disease, and amyotrophic lateral sclerosis, where it mediates profoundly different effects, ranging from neuroprotective to neurotoxic. Therefore, a more detailed understanding of Pin1 neuronal functions may provide relevant information on the consequences of Pin1 deregulation in age-related and neurodegenerative disorders.

Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases.

By controlling the change of the backbones of several cellular substrates, the peptidyl-prolyl cis-trans isomerase Pin1 acts as key fine-tuner and amplifier of multiple signaling pathways, thereby inducing several biological consequences, both in physiological and pathological conditions. Data from the literature indicate a prominent role of Pin1 in the regulating of vascular homeostasis. In this review, we will critically dissect Pin1's role as conformational switch regulating the homeostasis of vascular endothelium, by specifically modulating nitric oxide (NO) bioavailability. In this regard, Pin1 has been reported to directly control NO production by interacting with bovine endothelial nitric oxide synthase (eNOS) at Ser116-Pro117 (human equivalent is Ser114-Pro115) in a phosphorylation-dependent manner, regulating its catalytic activity, as well as by regulating other intracellular players, such as VEGF and TGF-ß, thereby impinging upon NO release. Furthermore, since Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many vascular diseases (e.g., diabetes, atherosclerosis, hypertension, and cardiac hypertrophy), evidence indicating that Pin1 may serve a pivotal role in vascular endothelium will be discussed. Understanding the role of Pin1 in vascular homeostasis is crucial in terms of finding a new possible therapeutic player and target in vascular pathologies, including those affecting the elderly (such as small and large vessel diseases and vascular dementia) or those promoting the full expression of neurodegenerative dementing diseases.