Effects of High BMI on Synaptic Function and Metabolic Connectivity in the Brain—Evidence of Gender Difference

Synapses play a central role for the processing of information in the brain and have been analyzed in countless biochemical, electrophysiological, imaging, and computational studies. The functionality and plasticity of synapses are nevertheless still difficult to predict, and conflicting hypotheses have been proposed for many synaptic processes. In this review, we argue that the cause of these problems is a lack of understanding of the spatiotemporal dynamics of key synaptic components. Fortunately, a number of emerging imaging approaches, going beyond super-resolution, should be able to provide required protein positions in space at different points in time. Mathematical models can then integrate the resulting information to allow the prediction of the spatiotemporal dynamics. We argue that these models, to deal with the complexity of synaptic processes, need to be designed in a sufficiently abstract way. Taken together, we suggest that a well-designed combination of imaging and modelling approaches will result in a far more complete understanding of synaptic function than currently possible.

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Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

Cells ◽

10.3390/cells8111314 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1314 ◽

Cited By ~ 7

Author(s):

Sen ◽

Almuslehi ◽

Gyengesi ◽

Myers ◽

Shortland ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

Immune System ◽

Adaptive Immune System ◽

Synaptic Function ◽

Adaptive Immune ◽

Splenic Atrophy ◽

The Impact ◽

The Brain ◽

Inside Out

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

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The impact of bilingualism on brain reserve and metabolic connectivity in Alzheimer's dementia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610909114 ◽

2017 ◽

Vol 114 (7) ◽

pp. 1690-1695 ◽

Cited By ~ 88

Author(s):

Daniela Perani ◽

Mohsen Farsad ◽

Tommaso Ballarini ◽

Francesca Lubian ◽

Maura Malpetti ◽

...

Keyword(s):

Neuroprotective Effect ◽

Alzheimer’S Dementia ◽

Synaptic Function ◽

Compensatory Mechanisms ◽

Neuroprotective Effects ◽

Alzheimer's Dementia ◽

Bilingual Speakers ◽

Metabolic Connectivity ◽

The Impact

Cognitive reserve (CR) prevents cognitive decline and delays neurodegeneration. Recent epidemiological evidence suggests that lifelong bilingualism may act as CR delaying the onset of dementia by ∼4.5 y. Much controversy surrounds the issue of bilingualism and its putative neuroprotective effects. We studied brain metabolism, a direct index of synaptic function and density, and neural connectivity to shed light on the effects of bilingualism in vivo in Alzheimer’s dementia (AD). Eighty-five patients with probable AD and matched for disease duration (45 German-Italian bilingual speakers and 40 monolingual speakers) were included. Notably, bilingual individuals were on average 5 y older than their monolingual peers. In agreement with our predictions and with models of CR, cerebral hypometabolism was more severe in the group of bilingual individuals with AD. The metabolic connectivity analyses crucially supported the neuroprotective effect of bilingualism by showing an increased connectivity in the executive control and the default mode networks in the bilingual, compared with the monolingual, AD patients. Furthermore, the degree of lifelong bilingualism (i.e., high, moderate, or low use) was significantly correlated to functional modulations in crucial neural networks, suggesting both neural reserve and compensatory mechanisms. These findings indicate that lifelong bilingualism acts as a powerful CR proxy in dementia and exerts neuroprotective effects against neurodegeneration. Delaying the onset of dementia is a top priority of modern societies, and the present in vivo neurobiological evidence should stimulate social programs and interventions to support bilingual or multilingual education and the maintenance of the second language among senior citizens.

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Transient receptor potential melastatin 2 governs stress-induced depressive-like behaviors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814335116 ◽

2019 ◽

Vol 116 (5) ◽

pp. 1770-1775 ◽

Cited By ~ 7

Author(s):

Seung Yeon Ko ◽

Sung Eun Wang ◽

Han Kyu Lee ◽

Sungsin Jo ◽

Jinil Han ◽

...

Keyword(s):

Chronic Stress ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Synaptic Function ◽

Tissue Samples ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

The Brain ◽

Synapsin 1

Major depressive disorder (MDD) is a devastating disease that arises in a background of environmental risk factors, such as chronic stress, that produce reactive oxygen species (ROS) in the brain. The chronic stress-induced ROS production involves Ca2+ signals; however, the mechanism is poorly understood. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+-permeable cation channel that is highly expressed in the brain. Here we show that in animal models of chronic unpredictable stress (CUS), deletion of TRPM2 (Trpm2−/−) produces antidepressant-like behaviors in mice. This phenotype correlates with reduced ROS, ROS-induced calpain activation, and enhanced phosphorylation of two Cdk5 targets including synapsin 1 and histone deacetylase 5 that are linked to synaptic function and gene expression, respectively. Moreover, TRPM2 mRNA expression is increased in hippocampal tissue samples from patients with MDD. Our findings suggest that TRPM2 is a key agent in stress-induced depression and a possible target for treating depression.

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PUFA and their derivatives in neurotransmission and synapses: a new hallmark of synaptopathies

Proceedings of The Nutrition Society ◽

10.1017/s0029665120000129 ◽

2020 ◽

Vol 79 (4) ◽

pp. 388-403

Author(s):

Mathieu Di Miceli ◽

Clémentine Bosch-Bouju ◽

Sophie Layé

Keyword(s):

Synapse Formation ◽

Synaptic Function ◽

Past Century ◽

High Concentration ◽

Dietary Pufa ◽

Synaptic Functions ◽

Neuropsychiatric Diseases ◽

Optimal Function ◽

The Brain

PUFA of the n-3 and n-6 families are present in high concentration in the brain where they are major components of cell membranes. The main forms found in the brain are DHA (22 :6, n-3) and arachidonic acid (20:4, n-6). In the past century, several studies pinpointed that modifications of n-3 and n-6 PUFA levels in the brain through dietary supply or genetic means are linked to the alterations of synaptic function. Yet, synaptopathies emerge as a common characteristic of neurodevelopmental disorders, neuropsychiatric diseases and some neurodegenerative diseases. Understanding the mechanisms of action underlying the activity of PUFA at the level of synapses is thus of high interest. In this frame, dietary supplementation in PUFA aiming at restoring or promoting the optimal function of synapses appears as a promising strategy to treat synaptopathies. This paper reviews the link between dietary PUFA, synapse formation and the role of PUFA and their metabolites in synaptic functions.

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Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Male and Female Mice

10.1101/2020.08.19.258236 ◽

2020 ◽

Cited By ~ 1

Author(s):

Andrea Stojakovic ◽

Su-Youne Chang ◽

Jarred Nesbitt ◽

Nicholas P. Pichurin ◽

Mark A. Ostroot ◽

...

Keyword(s):

Cognitive Function ◽

Glucose Metabolism ◽

Complex I ◽

Energy Homeostasis ◽

Synaptic Function ◽

Synaptic Activity ◽

Morris Water Maze Test ◽

Synaptic Dysfunction ◽

Male And Female ◽

The Brain

AbstractBackgroundAccumulation of hyperphosphorylated Tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown.ObjectiveTo investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on pTau levels, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms.MethodsCP2 was administered to male and female 3xTg-AD mice from 3.5 - 18 months of age. Cognitive function was assessed using the Morris water maze test. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting.ResultsChronic CP2 treatment restored synaptic activity and cognitive function, increased levels of synaptic proteins, improved glucose metabolism and energy homeostasis in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β).ConclusionCP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for AD.

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Inhibiting proBDNF to mature BDNF conversion leads to autism-like phenotypes in vivo

10.1101/2020.06.12.149104 ◽

2020 ◽

Author(s):

He You ◽

Toshiyuki Mizui ◽

Kazuyuki Kiyosue ◽

Keizo Takao ◽

Tsuyoshi Miyakawa ◽

...

Keyword(s):

Autism Spectrum ◽

Synaptic Function ◽

Early Age ◽

Mouse Line ◽

Brain Volumes ◽

Blood Marker ◽

Spectrum Disorders ◽

Neurodevelopment Disorders ◽

The Brain

AbstractAutism spectrum disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is oppositely regulated by brain-derived neurotrophic factor (BDNF): the precursor proBDNF inhibits while mature BDNF (mBDNF) potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is inhibited. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed decreased brain volumes, reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity. They also exhibited ASD-like phenotypes, including stereotypical behaviors, deficits in social interaction, hyperactivity, and elevated stress response. Interestingly, the plasma level of proBDNF, but not mBDNF, was significantly elevated in ASD patients. These results suggest that proBDNF level, but not Bdnf gene, is associated with autism-spectrum behaviors, and identify a potential blood marker and therapeutic target for ASD.

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Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength

10.1101/2021.04.30.441835 ◽

2021 ◽

Author(s):

A.M. Ramsey ◽

A.H. Tang ◽

T.A. LeGates ◽

X.Z. Gou ◽

B.E. Carbone ◽

...

Keyword(s):

Adhesion Molecule ◽

Ampa Receptors ◽

Glutamate Release ◽

Receptor Activation ◽

Synaptic Strength ◽

Synaptic Function ◽

The Novel ◽

Novel Concept ◽

The Brain

AbstractRecent evidence suggests that nanoorganization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this idea. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors, we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale de-clustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function, and support the novel concept that adhesion molecules acutely position AMPA receptors to dynamically control synaptic strength.

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Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

10.21203/rs.3.rs-29102/v1 ◽

2020 ◽

Author(s):

Sunny Kumar ◽

Daniel Phaneuf ◽

Pierre Cordeau ◽

Hejer Boutej ◽

Jasna Kriz ◽

...

Keyword(s):

Transgenic Mice ◽

Oral Administration ◽

Neurodegenerative Diseases ◽

Mouse Models ◽

Synaptic Function ◽

Neurofilament Proteins ◽

Type Iv ◽

One Year ◽

The Impact ◽

The Brain

Abstract Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

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Association between plasma phospho-tau181 and cognitive change from age 73 to 82: Lothian Birth Cohort 1936

10.1101/2021.11.24.469836 ◽

2021 ◽

Author(s):

Tyler S Saunders ◽

Amanda Heslegrave ◽

Declan King ◽

Sarah Harris ◽

Craig W Ritchie ◽

...

Keyword(s):

Cognitive Decline ◽

Cognitive Change ◽

Synaptic Function ◽

Blood Biomarker ◽

Array Tomography ◽

Age Related ◽

Lothian Birth Cohort ◽

Synapse Degeneration ◽

Age Related Cognitive Decline ◽

The Brain

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we tested whether plasma p-tau181predicts cognitive decline and whether it is present in synapses in human brain. METHODS: General cognitive ability and plasma p-tau181 concentration were measured in 195 participants at ages 72 and 82. Levels of p-tau181 in total homogenate and synaptic fractions were compared with western blot (n=10-12 per group), and synaptic localisation was examined using array tomography. RESULTS: Elevated baseline plasma p-tau181 and increasing p-tau181 over time predicted steeper general cognitive decline. We observe p-tau181 in neurites, presynapses, and post-synapses in the brain. DISCUSSION: Baseline and subsequent change in plasma p-tau181 may represent rare biomarkers of differences in cognitive ageing across the 8th decade of life and may play a role in synaptic function in the brain.

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