Amyloid-beta and tau protein beyond Alzheimer's disease

The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating disease.Physiologically,these two proteins are produced and expressed within the normal human body.However,under pathological conditions,abnormal expression,posttranslational modifications,conformational changes,and truncation can make these proteins prone to aggregation,triggering specific disease-related cascades.Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases,such as Alzheimer's disease,Parkinson's disease,and amyotrophic lateral sclerosis,as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration.Additionally,these proteins have been linked to cardiovascular disease,cancer,traumatic brain injury,and diabetes,which are all leading causes of morbidity and mortality.In this comprehensive review,we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

The Florey Institute of Neuroscience and Mental Health,

1Early history In1963the Howard Florey Laboratories were first established as a component of the Department of Physiology at the University of Melbourne.The laboratories quickly expanded under the founding directorship of Dr.Derek Denton and the funds were obtained with the philanthropic assistance of Sir Ian Potter and Mr.Ken Myer to create a new building on the south-west corner University site.This enabled the building to be opened in August1963.The Nobel laureate,Sir Howard Florey,well-known discoverer of the technique to mass-produce penicillin was pleased to lend his name to the new initiative,and was present at its opening with the Prime Minister,Sir Robert Menzies,and other dignitaries.

Optical tissue clearing enables rapid,precise and comprehensive assessment of three-dimensional morphology in experimental nerve regeneration research

Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections.Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain.To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats.The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence.The optical clearing was compatible with conventional laboratory techniques,including retrograde labeling studies,and computational image segmentation,providing fast and precise cell quantitation.Further,optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies,tracing of intramuscular nerve branches or mapping of neurovascular networks.Given their wide-ranging applicability,rapid processing times,and low costs,tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies.All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee(49871/9)on November 9,2019.

Pluripotent stem cell derived inhibitory interneurons–principles and applications in health and disease

Inhibitory interneurons are gamma-aminobutyric acid-ergic (GABAergic) nerve cells that act to maintain the appropriate excitation-inhibition balance, and synchronise the output of principle cells to generate rhythmic patterns of firing (Kessaris et al., 2014). This critical role, along with their brain-wide distribution, has led to the implication of interneurons in many neuropathologies, including schizophrenia, autism, dystonia and epilepsies (Marín, 2012).

Alexander disease:the road ahead

Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.

Time to forge ahead:The Internet of Things for healthcare

Situated at the intersection of technology and medicine,the Internet of Things(IoT)holds the promise of addressing some of healthcare's most pressing challenges,from medical error,to chronic drug shortages,to overburdened hospital systems,to dealing with the COVID-19 pandemic.However,despite considerable recent technological advances,the pace of successful implementation of promising IoT healthcare initiatives has been slow.To inspire more productive collaboration,we present here a simple—but surprisingly underrated—problemoriented approach to developing healthcare technologies.To further assist in this effort,we reviewed the various commercial,regulatory,social/cultural,and technological factors in the development of the IoT.We propose that fog computing—a technological paradigm wherein the burden of computing is shifted from a centralized cloud server closer to the data source—offers the greatest promise for building a robust and scalable healthcare IoT ecosystem.To this end,we explore the key enabling technologies that underpin the fog architecture,from the sensing layer all the way up to the cloud.It is our hope that ongoing advances in sensing,communications,cryptography,storage,machine learning,and artificial intelligence will be leveraged in meaningful ways to generate unprecedented medical intelligence and thus drive improvements in the health of many people.

Data and subject heterogeneity and data sharing:keys to translational success in spinal cord injury research?

Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the presynaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter(EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.

Biomarkers in schizophrenia:A focus on blood based diagnostics and theranostics

Identifying biomarkers that can be used as diagnostics or predictors of treatment response(theranostics) in people with schizophrenia(Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophreniaassociated phenotype. We sorted the studies into six categories which include:(1) brain-derived neurotrophic factor;(2) inflammation and immune function;(3) neurochemistry;(4) oxidative stress response and metabolism;(5) epigenetics and micro RNA; and(6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, bloodoriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.

How random is the random forest ? Random forest algorithm on the service of structural imaging biomarkers for Alzheimer's disease: from Alzheimer's disease neuroimaging initiative(ADNI) database

Neuroinformatics is a fascinating research field that applies computational models and analytical tools to high dimensional experimental neuroscience data for a better understanding of how the brain functions or dysfunctions in brain diseases. Neuroinformaticians work in the intersection of neuroscience and informatics supporting the integration of various sub-disciplines（behavioural neuroscience, genetics, cognitive psychology, etc.） working on brain research. Neuroinformaticians are the pathway of information exchange between informaticians and clinicians for a better understanding of the outcome of computational models and the clinical interpretation of the analysis. Machine learning is one of the most significant computational developments in the last decade giving tools to neuroinformaticians and finally to radiologists and clinicians for an automatic and early diagnosis-prognosis of a brain disease. Random forest（RF） algorithm has been successfully applied to high-dimensional neuroimaging data for feature reduction and also has been applied to classify the clinical label of a subject using single or multi-modal neuroimaging datasets. Our aim was to review the studies where RF was applied to correctly predict the Alzheimer＇s disease（AD）, the conversion from mild cognitive impairment（MCI） and its robustness to overfitting, outliers and handling of non-linear data. Finally, we described our RF-based model that gave us the 1 ^（st） position in an international challenge for automated prediction of MCI from MRI data.

Understanding the pathophysiology of postpartum psychosis: Challenges and new approaches

Postpartum psychosis is a severe psychiatric condition which affects 1-2 of every 1000 mothers shortly after childbirth. Whilst there is convincing evidence that the condition is precipitated by a complex combination of biological and environmental factors, as yet the pathophysiological mechanisms remain extremely poorly defined. Here, I critically review approaches that have been, or are being, employed to identify and characterise such mechanisms; I also review a recent animal model approach, and describe a novel biological risk model that it suggests. Clarification of biological risk mechanisms underlying disorder risk should permit the identification of relevant predictive biomarkers which will ensure that "at risk" subjects receive prompt clinical intervention if required.

High mobility group box protein 1 and white matter injury following traumatic brain injury: perspectives on mechanisms and therapeutic strategies

Traumatic brain injury(TBI)is a major cause of morbidity and mortality worldwide.Despite significant medical advances over recent decades,many survivors of TBI develop long term neuro-cognitive deficits.Previously,only moderate and severe injuries were thought to account for the devastating consequences of TBI.However,there is increasing evidence that even milder injuries may result in problematic lifelong cognitive and affective disturbances.TBI is typically characterized by an an acute physical injury followed by a protracted innate neuro-inflammatory response.These reponses,mediated via neuronal,astrocyte and microglial cells,amongst others,and may result in widespread neuronal death and a micro-environment that is not conducive to brain repair(Manivannan et al.,2021).Whilst the primary physical injury often evades intervention from a medical perspective,the subsequent neuro-inflammatory response offers a potential therapeutic target.Nonetheless,effective pharmacological strategies continue to elude clinicians and scientists due to the complex underlying pathogenesis and difficulties of modelling such a heterogeneous disease.However,the majority of research to date has focused on investigating the effects of post-traumatic neuro-inflammation on grey matter injury rather than the consequences upon white matter(WM),which contributes greatly to cognitive dysfunction across many neurological diseases(Filly and Kelly,2018).Herein,we will briefly discuss:(i)high mobility group box protein 1(HMGB1)as a potential therapeutic target;(ii)the relevance of WM injury in TBI and current understanding of WM repair following injury;and(iii)perspectives on how HMGB1 may play a role.

Virtual games and quality of life in Parkinson’s disease: A randomised controlled trial

Objective: To evaluate the efficacy of Nintendo Wii training in quality of life in Parkinson’s disease (PD) patients when compared to traditional physical therapy (PT). Methods: A randomized, single-blinded trial with 2 parallel arms was performed in a referral center for movement disorders in North-eastern, Brazil. Forty-four PD outpatients that fulfilled the eligibility criteria with mild to moderate motor impairment were randomized. Both groups executed a warm up session for 10 minutes that consisted of trunk flexion, extension and rotation, associated with upper and lower limbs stretching. The PT group followed a program that consisted of trunk and limb mobilisation, balance, muscle strengthening, rhythmic movement, postural alignment, double-task execution, bimanual tasks, and gait training. The Nintendo Wii group executed a sequence of tasks according to a previously established protocol, with similar training exercises. Duration of exercises was 40 minutes per session, 3 days per week for 4 weeks. The primary endpoint was the total score obtained in the Parkinson’s disease quality of life questionnaire (PDQ-39) translated from English to Brazilian Portuguese by Oxford outcomes. Secondary endpoints were the scores achieved by each group in the following domains of PDQ-39 scale: mobility, activities of daily living (ADL), emotional well-being, stigma, social support, cognition, communication and bodily discomfort. Assessments were performed before and after intervention in both groups with subjects in the “on” period. Results: Subjects in the Nintendo Wii group showed greater improvement in the PDQ-39 total score when compared to PT group (p = 0.01). Also, significant differences were observed in ADL, stigma, social support and communication when comparing subjects before and after intervention in the Nintendo Wii group (p < 0.05). Conclusions: The results achieved in this trial suggest that rehabilitation using Nintendo Wii may have beneficial effects in quality of life of PD subjects, when compared to traditional PT. Further larger randomised controlled-trials are necessary to reassure these results.

Cognitive, behavioural and psychiatric phenotypes associated with steroid sulfatase deficiency

The enzyme steroid sulfatase(STS)desulfates a variety of steroid compounds thereby altering their activity.STS is expressed in the skin,and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis.STS is also highly expressed in the developing and adult human brain,and in a variety of steroidogenic organs(including the placenta and gonads);therefore it has the potential to influence brain development and function directly and/or indirectly(through influencing the hormonal milieu).In this review,we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders.We subsequently discuss potential mechanisms that may underlie these vulnerabilities.The data described herein have potential implications for understanding the complete spectrum ofclinical phenotypes associated with X-linked ichthyosis,and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.

Alternative models for transgenerational epigenetic inheritance:Molecular psychiatry beyond mice and man

Mental illness remains the greatest chronic health burden globally with few inroads having been made despite significant advances in genomic knowledge in recent decades.The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations,and that has to be supported by a continuous growth in knowledge.The majority of neuropsychiatric symptoms reflect complex geneenvironment interactions,with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms.It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stressrelated behavioural phenotypes in both paternal and maternal lineages,providing further supporting evidence for heritability in humans.However,unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions.While rodents will remain the dominant model system for preclinical studies(especially for addressing complex behavioural phenotypes),there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models.Here,we will discuss the utility and advantages of two alternative model organisms–Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.

Brucine N-oxide reduces ethanol intake and preference in alcohol-preferring Fawn-Hooded rats

OBJECTIVE The alcoholism-related social problems have burdened the public health heavily.A better therapy for alcohol dependence as a chronic brain disease is highly required and interests the scientists worldwide. Our group has focused on screening the right drug with low toxicity and a sound curative effect from traditional Chinese medicine. METHODS Alcohol-preferring Fawn-Hooded(FH/Wjd) rat was used as an animal model of alcoholism to evaluate the effects of brucine N-oxide(BNO),an alkoloid naturally existing in the seeds of Strychnos nux-vomica L,on the alcohol-drinking behaviors.Furthermore,its adverse action and toxicity were investigated. RESULTS Treatment with BNO at the doses of 30,50 and 70 mg · kg^(-1)reduced the voluntary alcohol consumption and preference dosedependently and selectively without altering their water intake,total fluid intake,food consumption,body weight as well as sucrose preference. Remarkably,70 mg·kg^(-1)of BNO did suppress the deprivationinduced elevation of alcohol ingestion. Moreover,BNO used at the same doses as above had no influence on locomotion in an open field test and could not result in the place preference effect. CONCLUSION Taken together,BNO is of some significant pharmacological profiles to inhibit symptoms of alcohol dependence with high safety,and thence may be a potential pharmacotherapy.

Optimising validity and translational potential in rodent models of brain disorders

Neurological and psychiatric disorders collectively constitute the greatest burden of disease. However, the human brain is the most complex of biological systems and therefore accurately modeling brain disorders presents enormous challenges. A large range of therapeutic approaches across a diverse collection of brain disorders have been found to show great promise in preclinical testing and then failed during clinical trials. There are a variety of potential reasons for such failures, on both the preclinical and clinical sides of the equation. In this article, I wi l l focus on the key issues of validity in animal models. I wi l l discuss two forms of construct validity,‘genetic construct validity’ and ‘environmental construct val idity’,which model specific aspects of the genome and ‘envirome’ relevant to the disorder in question. The generation of new gene-edited animal models has been facilitated by new technologies, the most notable of which are CRISPR-Cas systems. These and other technologies can be used to enhance contruct validity. Finally, I wi l l discuss how face validity can be optimized, via more sophisticated cognitive, affective and motor behavioural tests, translational tools and the integration of molecular, cellular and systems data. Predictive validity cannot yet be assessed for the many preclinical models where we currently lack effective clinical interventions, however this wi l l change as the translational pipeline is honed to deliver therapies for a range of devastating disorders.

Evaluating visual outcomes using optical coherence tomography(OCT)in pediatric multiple sclerosis and other neuroinflammatory conditions

Optical coherence tomography(OCT)is a technology that is widely used to assess structural abnormalities in the retina for a variety of pediatric conditions.The introduction of this instrument has allowed for widespread access to minimally invasive standardized,reproducible quantified structural assessments of the optic nerve and retina.This has had important implications in pediatric optic neuropathies,populations in whom monitoring of disease activity is essential to make treatment decisions.OCT has had particular relevance for inflammatory optic neuropathies,as onset of an inflammatory optic neuropathy may herald the onset of a chronic inflammatory disorder of the central nervous system(CNS)such as multiple sclerosis,neuromyelitis optica spectrum disorder(aquaporin 4 antibody positive),and myelin oligodendrocyte glycoprotein(MOG)associated disorders.This paper will focus on the application of OCT technology to this group of disorders in pediatrics.After reviewing pediatric-specific anatomic and practical issues pertinent to OCT,we will review knowledge related to the use of OCT in inflammatory pediatric optic neuropathies,with a focus on structural outcomes and their correlation with functional outcome metrics.

S2B-2 Comorbidity of Anxiety and Depression Induced by Liang’s Contextual-Stress Box in Mice

Rationale:Comorbidity of depression and anxiety is one of the most common mental disorders in practice.Few experimental procedures,however,have focused on identifying mixed depression-and anxiety-like behaviors in animal models.Objectives:To develop a novel testing paradigm,the so-called Liang’s contextual-stress Box(briefly,Liang’s Box),for evaluating depression-and/or anxiety-like behaviors in mice.Methods:Liang’s Box consisted of a central area(CA)with three peripheral arms(PA).Mice were placed individually in the end of a peripheral arm facing to the central area and were allowed to travel around Liang’s Box.During a test period,behavioral parameters were recorded and collected by a video-tracking system named SMART 3.0(Panlab,Spain),including①Latency to CA,②Time spent in CA(CA-time),③Distance traveled in CA(CA-distance),④Distance traveled in PA(PA-distance),⑤Transition number between CA and PA,⑥Global activity,⑦CA-time/cm2,⑧PA-time/cm2,⑨CAdistance/cm2,and⑩PA-distance/cm2.In order to assess the reliability and validity of Liang’s Box and get baseline information,we undertook a series of experiment,including verifying consistency and stability in the various strains of mice(KM,ICR,and C57 BL/6 J mice),imposing high illumination,restraint and tail suspension stress,pre-treating with an anxiolytic(diazepam,buspirone)or antidepressant(desipramine,mianserin).Results:①There were not remarkable differences in all the parameters among KM,ICR,and C57 BL/6 J mice;②High illumination,restraint and tail suspension significantly increased the latency to CA and decreased the CA-time,CA-distance and transition number.However,these three types of stresses evoked different effect on global activity.High illumination increased activity,but restraint stress had no significant influence.In contrast with high illumination,tail suspension stress markedly reduced activity in mice;③The anxiolytics diazepam(0.25 mg·kg-1 and 0.5 mg·kg-1,i.p.)and buspirone(0.5 mg·kg-1 and 1.0 mg·kg-1,i.p.)significantly decreased latency to CA and transition number,and dosedependently increased the CA-time.However,they did not affect CA-or PA-distance,or global activity;④The antidepressants desipramine(10.0 mg·kg-1 and 30.0 mg·kg-1,i.p.)and mianserin(0.25 mg·kg-1 and 0.5 mg·kg-1,i.p.)significantly decreased latency to CA,and dose-dependently enhanced CA-time,CA-distance and transition number,while neither affected PA-distance or global activity.Conclusion:Our data suggest that Liang’s Box is a useful experimental instrument and method for screening and assessing potential antidepressants and/or anxiolytics.Moreover,depression-and anxiety-like behaviors induced by Liang’s Box in mice may be a new hybrid animal model to investigate the pathogenic mechanisms underlying the comorbidity of anxiety and depression.