All Articles

Lingyu Qiu, Huiqiang Lu*

Neuronal apoptosis is an important pathophysiological factor of Alzheimer’s disease (AD). Inhibition of endoplasmic reticulum stress (ERS)-induced neuronal apoptosis is an effective strategy to deal with AD. In this commentary, we summarize the relationship between AD and ERS injury-induced neuronal apoptosis, and highlight the protective effects and mechanism of isorhamnetin (Iso) against ERS-induced injury in N2a cells. Moreover, this commentary discusses the recent findings in the role of Iso in other diseases.

Fritz-Olaf Lehmann, PhD

Rhythmic locomotor behavior in animals requires exact timing of muscle activation within the locomotor cycle. Neural strategies for timing control that employ higher brain function, however, suffer from synaptic and neural transmission delays, making them inefficient for control of fast-frequent locomotor systems. Evolutionary pressure on muscle timing control is particularly pronounced in flying insects with wing flapping periods of few milliseconds. In these animals, sensory integration is often achieved at the level of the peripheral nervous system, circumventing the central brain and controlling spike activation phases with little delay, rather than muscle spike frequency. This review is engaged in the precision with which flies adjust power output of their flight muscles and highlights the significance of visual and proprioceptive feedback loops for muscle spike control. Recent results suggest that in flies peripheral feedback loops are keys enabling precise heading control and body stability in flight, and potentially similar to the function of local circuits for locomotor control found in the spinal chord of vertebrates.

Tomoyuki Nishizaki*

Alzheimer’s disease (AD) is characterized by extensive deposition of amyloid β (Aβ) and formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau. So far, a variety of AD drugs targeting Aβ have been developed, but ended in failure. A recent focus on AD therapy, therefore, is development of Tau-targeted drugs. Aβ activates glycogen synthase kinase-3β (GSK-3β), that plays a central role in Tau phosphorylation, responsible for NFT formation. The linoleic acid derivative DCP-LA has been developed as a promising drug for AD therapy. DCP-LA serves as a selective activator of PKCε and a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA restrains Tau phosphorylation efficiently due to PKCε-mediated direct inactivation of GSK-3β, to PKCε/Akt-mediated inactivation of GSK-3β, and to receptor tyrosine kinase/insulin receptor substrate 1/phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/Akt-mediated inactivation of GSK-3β in association with PTP1B inhibition. Moreover, DCP-LA ameliorates spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. Consequently, combination of PKCβ activation and PTP1B inhibition must be an innovative strategy for AD therapy.

Nishant Ranjan Chauhan¹, Rajinder Kumar Gupta¹, Shashi Bala Singh^2*

Heat stress (HS) is a common stressor that affects all biological systems. Mild to moderate HS is associated with intact baroreflex response which tries to cope up with the stress by maintaining mean arterial pressure (MAP). However, during severe HS, baroreflex response fails leading to fall in MAP which is a pathognomonic feature of heat stroke. Heat stroke can induce neuroinflammation, brain ischemia, oxidative stress and neuronal damage. Increase in ambient temperature led to activation of the thermoregulatory process in Hypothalamus (HTH) and was achieved by rise in nor-epinephrine and fall in serotonin, whereas neurotransmitter imbalance occurred during severe HS in HTH and was associated with expression of inflammatory mediators. Results of our preliminary study also suggested that neuroinflammation was associated with neurotransmitter (monoamines and glutamate) imbalance in HTH leading to thermoregulatory disruption during severe HS. Here, we also discussed that individuals predisposed to factors like chronic inflammation and other complications could decrease the threshold of heat tolerance since a short episode of even sub maximal heat exposure would precipitate the inflammatory cascade leading to thermoregulatory shutdown.

Francisco José Sanz^1,2, Cristina Solana-Manrique^1,2, Verónica Muñoz-Soriano^1,2 and Nuria Paricio^1,2,*

Takako Takemiya

^{Medical Research Institute, Tokyo Women’s Medical University, Shinjuku, Tokyo 162-8666, Japan}

Astrocytes interact closely with neurons via glutamate; this astrocyte-neuron circuit may play a pivotal role in synaptic transmission. In addition, astrocytes contact vascular endothelial cells (ECs) with their end-feet; therefore, ECs may have some role in regulating neuronal activity via astrocytes in the brain. In our studies, we found that kainic acid (KA) microinjection induced the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in venous ECs and the expression of the prostaglandin E₂ (PGE₂) receptor EP3 on astrocytes. Moreover, endothelial mPGES-1 exacerbated KA-induced neuronal injury in the mouse brain. In in vitro experiments, mPGES-1 produced PGE₂, which increased astrocytic Ca²⁺ levels and Ca²⁺-dependent glutamate release, thus aggravating neuronal injury. We found ECs had a role under pathological conditions and brain ECs are not merely a physiological barrier between the blood and brain; instead, they may also act as a signal transducer or amplifier. Moreover, the endothelium-astrocyte-neuron signaling pathway may be crucial for driving neuronal injury elicited by repetitive seizures and may be a new therapeutic target for epilepsy.

José M. Brito-Armas and Rafael Castro-Fuentes*

Benoit Michot¹

Marilene Demasi and Bruna Franciele Faria

Since the discovery of the proteasome (1986), many years passed before researchers explored the benefits of its activation. However, its inhibition, which was first observed in the beginning of the 1990s, gained wide acceptance because of its anti-tumor effect, as proteasome inhibition induces apoptosis. Currently, a proteasome inhibitor is utilized as a clinical tool. However, proteasome activation has been shown to either extend the life span of many cellular and animal models or prevent the accumulation of protein aggregates. Later effect might have an important contribution to neurodegenerative diseases with the hallmark of protein aggregation and the impairment of the proteasome. This short review presents prominent data on proteasome activation, focusing on the 20S catalytic proteasome particle. In addition, the benefits and consequences of proteasome activation in tumor development and progression are discussed.

Zui Narita¹ and Yuma Yokoi¹

Willeke M. Menks¹, Christina Stadler¹ and Nora M. Raschle¹

Antisocial behavior in youths constitutes a major public health problem worldwide. Conduct disorder is a severe variant of antisocial behavior with higher prevalence rates for boys (12%) as opposed to girls (7%). A better understanding of the underlying neurobiological mechanisms of conduct disorder is warranted to improve identification, diagnosis, or treatment. Functional and structural neuroimaging studies have indicated several key brain regions within the limbic system and prefrontal cortex that are altered in youths with conduct disorder. Examining the structural connectivity, i.e. white matter fiber tracts connecting these brain areas, may further inform about the underlying neural mechanisms. Diffusion tensor imaging (DTI) is a non-invasive technique that can evaluate the white matter integrity of fiber tracts throughout the brain. To date, DTI studies have found several white matter tracts that are altered in youths with conduct disorder. However, a majority of these studies have focused on male or mixed-gender groups, and only a few studies have specifically investigated white matter alterations in girls with conduct disorder. Ultimately, studies that directly compare boys and girls with conduct disorder are necessary to identify possible sexual dimorphic neural alterations and developmental trajectories of conduct disorder in youths.

Caroline Lücke^1*, Alexandra P. Lam¹, Helge H. O. Muller¹, Alexandra Philipsen^1,2

Cognitive behavioral therapy (CBT) is the standard form of psychotherapy currently used in adult attention deficit hyperactivity disorder (ADHD). However, biographical factors, such as chronic negative feedback in childhood, which may likely play a role in ADHD as a developmental disorder, are usually not substantially addressed by CBT. In recent years, schema therapy has received increasing attention as an effective therapy approach for chronic psychiatric disorders. A core feature of schema therapy is the identification and targeting of early maladaptive schemas, which are dysfunctional patterns and beliefs resulting from childhood experiences. Recently, two studies have demonstrated an increased prevalence of maladaptive schemas in adult ADHD. Thus, schema therapy might constitute a potentially promising approach in the treatment of ADHD, especially with regard to secondary problems such as poor coping strategies or impaired self-perception. However, randomized controlled clinical studies are needed to support that theory. Here, we provide an overview on the topic of biography-oriented therapy approaches in relation to adult ADHD, summarize current literature and discuss implications for future research.

Maggie M. K. Wong¹, Lauren M. Watson¹ and Esther B. E. Becker¹

The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

Lauren M. Wolf,¹ Shannon L. Servoss,² and Melissa A. Moss^1,3,*

In recent decades, the increasing prevalence of age-associated neurodegenerative diseases has underscored the need for targeted therapeutic strategies and novel diagnostics. Peptide-based neurotherapeutics offer high specificity and tolerability but are limited by proteolytic degradation in vivo. Peptoids, or N-substituted glycines, are versatile peptidomimetics that evade proteolytic degradation yet maintain many qualities that render peptides attractive neurotherapeutic candidates. These molecules may be engineered to their application through modifications that enhance structural stability and reactivity and can withstand various physiological stressors to retain their intended function within anomalous microenvironments.

Peptoids generally demonstrate greater cellular permeability than their corresponding peptides, are less immunogenic, and can be administered intranasally, all properties that enhance their potential as neurotherapeutics. Peptoids have primarily been explored as aggregation inhibitors to prevent the deleterious protein plaque deposition associated with several neurodegenerative disorders. However, novel research has uncovered the potential of peptoids toward additional neurotherapeutic applications. Peptoids can modulate cell signaling pathways involved in axonal function and current modulation and can block cell signaling events associated with apoptosis. In addition, these peptidomimetics are able to function as anti- inflammatory agents via multiple mechanisms. Moreover, the versatility and low cost of peptoids render them ideal instruments in biomarker detection, discovery, and imaging. This mini-review explores these diverse applications of peptoids within the context of neurodegenerative disease.

Shinji Ohara

Acute disseminated encephalomyelitis (ADEM) and Multiple sclerosis (MS) are both immunologically mediated inflammatory demyelinating disease of the CNS. ADEM and MS have long been considered as a separate disease entities, but clinical differentiation of ADEM from the first attack of MS is often difficult because of overlapping clinical features. Pathologically, perivenous demyelination and discrete confluent demyelination (plaque) have been generally regarded as the hallmark of ADEM and MS, respectively. It is also known that in contrast to MS, which shows quite diverse heterogeneous pathologic patterns, ADEM shows generally homogenous pathological features of inflammatory demyelination. However, hybrid cases showing pathological features of both ADEM and MS do exist, suggesting that ADEM may share some common underlying pathologic mechanisms with certain stages or subgroups of MS.

Jun Sun

Shun Aritake, Hiroaki Oguro*, Kenichi Iwasa, Shingo Mitaki, Hiroyuki Takayoshi, Satoshi Abe, Keiichi Onoda, Shuhei Yamaguchi

We studied prognosis in 156 acute stoke patients treated by ozagrel and edaravone with the Japanese Standard Stroke Registry database in our hospital. They were examined as to their stroke types, neurological severity according to the NIH Stroke Scale (NIHSS) and clinical outcomes at admission by the modified Rankin Scale (mRS).  Acute noncardioembolic stroke patients with lacunar and atherothrombosis showed functional recovery by both of ozagrel monotherapy and the combination therapy of ozagrel and edaravone. Although ozagrel monotherapy in atherothrombotic infarction showed most improved by 2.4 points, we did not find significant difference among four groups according to ozagrel monotherapy or the combination therapy in atherothrombotic or lacunar infarct after adjusted for age. 

Norishi Ueda

We previously reviewed clinical characteristics of all reported pediatric cases of Mycoplasma pneumonia (M.pneumoniae)-associated mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). It dominantly occurs in Asian and Caucasian children, suggesting age/race as predisposing factors of MERS. Fever is the most common non-neurological symptom, while more than half of the cases have no respiratory symptoms. Thus, M.pneuminiae-associated MERS may be underestimated and should be a differential diagnosis of febrile children with neurological abnormalities. The mechanism of the disease is unknown. However, susceptibility of immature corpus callosum in young children to immune response-mediated neuroinflammattory stimuli induced by M.pneuminiae, including interleukin-6, reactive oxygen species and toll-like receptors, rather than direct invasion of the organism in central nervous system may contribute to the pathogenesis of MERS. A role of autoantibodies awaits further investigations. Despite excellent prognosis in type I MERS, it remains elusive whether type II MERS is highly associated with neurological sequel.

Chiara Stella Di Stadio¹, Filomena Altieri¹, Giuseppina Minopoli¹, Giuseppina Miselli¹, Emilia Rippa^1*, Paolo Arcari^1,2*

Gastrokine 1 (GKN1) is a 18 kDa stomach protein highly expressed in normal gastric tissue but absent in gastric cancer. GKN1 plays its major role in maintaining gastric mucosal integrity. Because of the presence in its central region of a BRICHOS domain, GKN1 is characterized by multifunctional properties since it interacts and regulates the activity of several proteins. The BRICHOS domain consists of about 100 amino acids and has been found in protein families often associated with major human diseases like familial British and Danish dementia (BRI2) or respiratory distress syndrome (surfactant protein C) (SP-C), both associated with amyloid formation. It has been shown that BRICHOS is a chaperon domain that has the property of binding precursor protein regions with high β-sheet tendencies, thereby preventing them from amyloid formation. Like the BRICHOS domains from BRI2 and SP-C precursor (proSP-C), also GKN1 is able to prevent fibrils formation of amyloid-beta peptide (Aβ) and to interact with the C-terminal region of APP thus hindering the γ-secretase proteolytic sites. Indeed, amyloid is of great medical importance since it originates in several major fatal diseases such as Alzheimer, Parkinson and diabetes mellitus. The results collected until now on the BRICHOS properties of GKN1 and those from other BRICHOS suggest that the different amyloids recognized by BRICHOS should contain similar structural elements therefore, the BRICHOS domain represents a potential powerfull tool for therapeutic approaches against amyloid associated diseases.

Abbreviations: AD, Alzheimer disease; Aβ, amyloid-beta peptide; APP, amyloid precursor protein; CTFs, APP C-Terminal Fragments; GC, gastric cancer; DAPT, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; DMSO, dimethyl sulfoxyde; GC, gastric cancer; GKN1, gastrokine 1; flGKN1, full-lenght GKN1; MS, mass spectrometry; rGKN1, recombinant GKN1; SPR, surface plasma resonance; TM, transmembrane; TMpred, transmembrane prediction.

Le Gjerum & Mette Midttun*

Chiara Cupidi, Valentina Laganà, Nicoletta Smirne, Amalia Cecilia Bruni*

Yoon-Sang Oh, Dong-Woo Ryu, Jee-Eun Lee, Joong-Seok Kim^*

Cognitive dysfunction and dementia are important causes of disability and mortality in the elderly population. Over a decade, many studies have found evidence that greater arterial stiffness is associated with impaired cognitive function. Stiff arteries have a direct effect on the brain microvasculature. In this review, we present evidence that arterial stiffness is linked to cognitive dysfunction in neurodegenerative disorders represented by Alzheimer’s disease and Parkinson’s disease. We also discuss possible mechanisms of arterial stiffness and cognitive dysfunction other than the universal pathologic features of beta-amyloid for Alzheimer’s disease and alpha-synuclein for Parkinson’s disease.

Soon Young Park, Veerakumar Balasubramaniyan, and John F. de Groot^*

Tarek Nafee, Dima Nimri, Gerald Chi, Serge Korjian, Yazan Daaboul, Douglas Arbetter, Megan Yee, Purva Jain, Seyedmahdi Pahlavani, Haleigh Williams, Nathan Michalak, Megan Merlo, Usama Talib, C. Michael Gibson*

Stroke is one of the leading causes of mortality and morbidity worldwide. It results in considerable costs to the healthcare system in the United States. Pharmacologic stroke prophylaxis has been well-studied in patients with atrial fibrillation and in patients with a history of stroke. In-hospital strokes constitute 2.2% to 17% of all strokes and often go undiagnosed in acute medically ill patients. A retrospective analysis of the APEX trial identifies an acutely ill hospitalized patient population that may benefit from extended duration prophylaxis. The hospitalized medically ill are a novel population to target for stroke prophylaxis. This article will discuss the primary results of the APEX sub-study and other trials that have demonstrated stroke reduction with extended duration anticoagulation in this population. This article additionally comments on the clinical relevance of these findings and the importance of the development of short-term risk stratification models to aid clinicians in deciding whether or not to provide pharmacologic stroke prophylaxis to their acutely ill patients at hospital admission.

Julien Leblond¹, Anne-Claude Juillerat Van der Linden^1,2, and Martial Van der Linden^1,3*

The dominant biomedical position considers Alzheimer’s disease (AD) to be intrinsically different from normal ageing and other neurodegenerative diseases and proposes that, by pursuing extensive research on what are considered the specific neuropathological characteristics of AD (i.e., neurotic plaques and neurofibrillary tangles), we will eventually be able to identify the cause of this disease and develop medical treatments that will allow us to successfully cure it. However, results of numerous recent studies go against this essentialist and category-based view and instead suggest that the cognitive, emotional, behavioural, and functional difficulties that some people experience as they grow older are modulated by a myriad of factors and mechanisms that interact throughout the lifespan. Importantly, this alternative way of conceptualising Alzheimer’s disease implies a shift of focus in terms of research objectives and calls for significant changes in terms of neuropsychological assessment and intervention in clinical practice.