Leptin: A Novel Therapeutic Target in Alzheimer's Disease?

It is well established that the hormone leptin circulates in the plasma in amounts proportional to body fat content and it regulates food intake and body weight via its actions in the hypothalamus. However, numerous studies have shown that leptin receptors are widely expressed throughout the CNS and evidence is growing that leptin plays a role in modulating a variety of neuronal processes. In particular, recent studies have highlighted a potential cognitive enhancing role for leptin as it regulates diverse aspects of hippocampal synaptic function that are thought to underlie learning and memory processes including glutamate receptor trafficking, dendritic morphology, and activity-dependent synaptic plasticity. Characterisation of the novel actions of leptin in limbic brain regions is providing valuable insights into leptin’s role in higher cognitive functions in health and disease.

Download Full-text

Leptin regulation of hippocampal synaptic function in health and disease

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0155 ◽

2014 ◽

Vol 369 (1633) ◽

pp. 20130155 ◽

Cited By ~ 61

Author(s):

Andrew J. Irving ◽

Jenni Harvey

Keyword(s):

Therapeutic Potential ◽

Brain Regions ◽

Neuronal Morphology ◽

Synaptic Function ◽

Leptin Receptors ◽

Cellular Events ◽

Endocrine Hormone ◽

Glutamate Receptor Trafficking ◽

Health And Disease ◽

Dependent Learning

The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.

Download Full-text

Regulation of glutamate receptor trafficking by leptin

Biochemical Society Transactions ◽

10.1042/bst0371364 ◽

2009 ◽

Vol 37 (6) ◽

pp. 1364-1368 ◽

Cited By ~ 19

Author(s):

Peter R. Moult ◽

Jenni Harvey

Keyword(s):

Synaptic Plasticity ◽

Ampa Receptors ◽

Long Term Potentiation ◽

Dendritic Morphology ◽

Receptor Trafficking ◽

Synaptic Function ◽

Hippocampal Synaptic Plasticity ◽

Glutamate Receptor Trafficking ◽

The Impact

It is well established that leptin is a circulating hormone that enters the brain and regulates food intake and body weight via its hypothalamic actions. However, it is also known that leptin receptors are widely expressed in the CNS (central nervous system), and evidence is accumulating that leptin modulates many neuronal functions. In particular, recent studies have indicated that leptin plays an important role in the regulation of hippocampal synaptic plasticity. Indeed leptin-insensitive rodents display impairments in hippocampal synaptic plasticity and defects in spatial memory tasks. We have also shown that leptin facilitates the induction of hippocampal LTP (long-term potentiation) via enhancing NMDA (N-methyl-D-aspartate) receptor function and that leptin has the ability to evoke a novel form of NMDA receptor-dependent LTD (long-term depression). In addition, leptin promotes rapid alterations in hippocampal dendritic morphology and synaptic density, which are likely to contribute to the effects of this hormone on excitatory synaptic strength. Recent studies have demonstrated that trafficking of AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors is pivotal for activity-dependent hippocampal synaptic plasticity. However, little is known about how AMPA receptor trafficking processes are regulated by hormonal systems. In the present paper, we discuss evidence that leptin rapidly alters the trafficking of AMPA receptors to and away from hippocampal CA1 synapses. The impact of these leptin-driven changes on hippocampal excitatory synaptic function are discussed.

Download Full-text

Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

Journal of Functional Morphology and Kinesiology ◽

10.3390/jfmk6020048 ◽

2021 ◽

Vol 6 (2) ◽

pp. 48

Author(s):

Elisa Innocenzi ◽

Ida Cariati ◽

Emanuela De Domenico ◽

Erika Tiberi ◽

Giovanna D’Arcangelo ◽

...

Keyword(s):

Alternative Splicing ◽

Aerobic Exercise ◽

Frontal Cortex ◽

Molecular Mechanisms ◽

Splice Variants ◽

Brain Regions ◽

Synaptic Function ◽

Molecular Changes ◽

Beneficial Effects ◽

The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

Download Full-text

Deep-MEG: spatiotemporal CNN features and multiband ensemble classification for predicting the early signs of Alzheimer’s disease with magnetoencephalography

Neural Computing and Applications ◽

10.1007/s00521-021-06105-4 ◽

2021 ◽

Author(s):

Antonio Giovannetti ◽

Gianluca Susi ◽

Paola Casti ◽

Arianna Mencattini ◽

Sandra Pusil ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Regions ◽

Ensemble Classification ◽

The Novel ◽

Ensemble Classifiers ◽

Deep Convolutional Neural Networks ◽

Early Signs ◽

Data Representations ◽

The Brain

AbstractIn this paper, we present the novel Deep-MEG approach in which image-based representations of magnetoencephalography (MEG) data are combined with ensemble classifiers based on deep convolutional neural networks. For the scope of predicting the early signs of Alzheimer’s disease (AD), functional connectivity (FC) measures between the brain bio-magnetic signals originated from spatially separated brain regions are used as MEG data representations for the analysis. After stacking the FC indicators relative to different frequency bands into multiple images, a deep transfer learning model is used to extract different sets of deep features and to derive improved classification ensembles. The proposed Deep-MEG architectures were tested on a set of resting-state MEG recordings and their corresponding magnetic resonance imaging scans, from a longitudinal study involving 87 subjects. Accuracy values of 89% and 87% were obtained, respectively, for the early prediction of AD conversion in a sample of 54 mild cognitive impairment subjects and in a sample of 87 subjects, including 33 healthy controls. These results indicate that the proposed Deep-MEG approach is a powerful tool for detecting early alterations in the spectral–temporal connectivity profiles and in their spatial relationships.

Download Full-text

Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

10.1101/2020.09.14.20190538 ◽

2020 ◽

Author(s):

Irene Lobon ◽

Manuel Solis-Moruno ◽

David Juan ◽

Ashraf Muhaisen ◽

Federico Abascal ◽

...

Keyword(s):

Parkinson Disease ◽

Somatic Mutations ◽

Amplicon Sequencing ◽

Brain Regions ◽

Single Nucleotide Variants ◽

Validation Rate ◽

Synaptic Functions ◽

Whole Exome ◽

Neuronal Processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. To explore their relevance in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and extensive filtering. We validated 27 of them with amplicon-based deep sequencing, with a 70% validation rate for the highest-confidence variants. Most of the sSNVs were exclusively called in blood but were also found in the brain tissues with the ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. We could confirm between 0 and 6 sSNVs per patient and generally those with a shorter lifespan carried more variants. Remarkably, the validated sSNVs are enriched in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease.

Download Full-text

Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

10.1101/2020.10.23.352310 ◽

2020 ◽

Author(s):

Matthew J. Van Hook ◽

Corrine Monaco ◽

Jennie C. Smith

Keyword(s):

Mouse Models ◽

Ganglion Cells ◽

Brain Regions ◽

Synaptic Function ◽

Homeostatic Plasticity ◽

Dorsal Lateral Geniculate Nucleus ◽

Intrinsic Excitability ◽

Dependent Manner ◽

Functional Changes ◽

Genetic Mouse Model

AbstractHomeostatic plasticity plays important roles in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes relate to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma – the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, but not younger D2 mice or microbead-injected mice. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in both ages of D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner in older D2 mice. Among D2 mice, functional changes observed in younger mice without elevated IOP were distinct from those observed in older mice with elevated IOP and RGC degeneration, suggesting that glaucoma-associated changes to neurons in the dLGN might represent a combination of stabilizing/homeostatic plasticity at earlier stages and pathological dysfunction at later stages.

Download Full-text

A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes

Molecular Neurobiology ◽

10.1007/s12035-021-02610-8 ◽

2021 ◽

Author(s):

Eva Haas ◽

Rana D. Incebacak ◽

Thomas Hentrich ◽

Chrisovalantou Huridou ◽

Thorsten Schmidt ◽

...

Keyword(s):

Mouse Model ◽

Brain Regions ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

The Novel ◽

Spinocerebellar Ataxia Type 3 ◽

Transcriptional Changes ◽

Cerebellar Tissue ◽

Type 3 ◽

Polyq Expansion

AbstractSpinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.

Download Full-text

The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease

Advances in Nutrition ◽

10.3945/an.115.011130 ◽

2017 ◽

Vol 8 (1) ◽

pp. 173S-181S ◽

Cited By ~ 60

Author(s):

María E Frigolet ◽

Ruth Gutiérrez-Aguilar

Keyword(s):

Palmitoleic Acid ◽

The Novel ◽

Health And Disease

Download Full-text

Face masks are an essential tool to mitigate the ongoing SARS-CoV-2 pandemic: a call to action

Rhinology online ◽

10.4193/rhinol/20.065 ◽

2020 ◽

Vol 3 (3) ◽

pp. 157-159

Author(s):

P. Dehgani-Mobaraki ◽

A. Kamber Zaidi ◽

J.M. Levy ◽

Keyword(s):

Upper Airway ◽

World Health ◽

Contact Tracing ◽

The Novel ◽

Call To Action ◽

Public Health Emergencies ◽

Current Spread ◽

The World ◽

Health And Disease ◽

Novel Coronavirus

Over the past several months, an increasing volume of infor- mation has expanded awareness regarding the transmission of SARS-CoV-2, the novel coronavirus associated with COVID-19. Following the pandemic declaration by the World Health Orga- nization (WHO), global authorities immediately took measures to reduce the transmission and subsequent morbidity associa- ted with this highly contagious disease. However, despite initial success in “flattening the curve” of viral transmission, many areas of the world are currently experiencing an increase in com- munity transmission, threatening to replicate the early public health emergencies experienced by Italy (1,2). In addition, the possibility of contact tracing through geosocial applications and public service platforms have been met with variable interest (3). Given current spread and the upcoming influenza season, it is essential that we use our voices as experts in upper airway health and disease to educate and encourage all communities to adopt appropriate protective measures, including the routine use of facemasks.

Download Full-text