CD200-, CX3CL1-, and TREM2-mediated neuron-microglia interactions and their involvements in Alzheimer’s disease

Abstract Neurons and microglia are two major components in the central nervous system (CNS). The interactions between them play important roles in maintaining homeostasis of the brain. In recent years, substantial studies have focused on the interactions between neurons and microglia, revealing that microglia become reactive when the interactions are pathophysiologically interfered, usually accompanying neuronal injury, which is a common feature for Alzheimer’s disease (AD). Many molecules and factors participate in these physiological and pathological processes, either in a contact-dependent or a contact-independent manner. Accumulating studies have revealed that in the CNS, cluster of differentiation-200 (CD200) and fractalkine (CX3CL1) expressed mainly on neurons and triggering receptor expressed on myeloid cells 2 (TREM2) expressed mainly on microglia. These molecules can mediate neuron-microglia interactions in a contact-dependent manner and contribute to the pathogenesis of AD. Here, we review the expression, distribution, and function of CD200, CX3CL1, and TREM2 in regulating neuron-microglia interactions under physiological conditions as well as in AD.

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Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

Neural Plasticity ◽

10.1155/2015/167308 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Sylwia Owczarek ◽

Marie Louise Bang ◽

Vladimir Berezin

Keyword(s):

Central Nervous System ◽

Cell Adhesion Molecules ◽

Synaptic Membranes ◽

Dependent Manner ◽

Related Protein ◽

Synaptic Complex ◽

The Central Nervous System ◽

And Function ◽

Activity Dependent ◽

The Brain

Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of theNX1andNX3genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1βcan regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.

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Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205015666180904155908 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1179-1190 ◽

Cited By ~ 21

Author(s):

Vilma M. Junges ◽

Vera E. Closs ◽

Guilherme M. Nogueira ◽

Maria G.V. Gottlieb

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Central Nervous System ◽

Nervous System ◽

Gut Microbiota ◽

System A ◽

Bidirectional Communication ◽

The Central Nervous System ◽

The Brain

The role of diet and gut microbiota in the pathophysiology of neurodegenerative diseases, such as Alzheimer's, has recently come under intense investigation. Studies suggest that human gut microbiota may contribute to the modulation of several neurochemical and neurometabolic pathways, through complex systems that interact and interconnect with the central nervous system. The brain and intestine form a bidirectional communication axis, or vice versa, they form an axis through bi-directional communication between endocrine and complex immune systems, involving neurotransmitters and hormones. Above all, studies suggest that dysbiotic and poorly diversified microbiota may interfere with the synthesis and secretion of neurotrophic factors, such as brain-derived neurotrophic factor, gammaaminobutyric acid and N-methyl D-Aspartate receptors, widely associated with cognitive decline and dementia. In this context, the present article provides a review of the literature on the role of the gutbrain axis in Alzheimer's disease.

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Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

Cells ◽

10.3390/cells10040957 ◽

2021 ◽

Vol 10 (4) ◽

pp. 957

Author(s):

Brad T. Casali ◽

Erin G. Reed-Geaghan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cells ◽

Expression Patterns ◽

Brain Parenchyma ◽

Primary Role ◽

And Function ◽

Inflammatory Milieu ◽

The Brain ◽

Homeostatic State

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.

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Astrocytic transporters in Alzheimer's disease

Biochemical Journal ◽

10.1042/bcj20160505 ◽

2017 ◽

Vol 474 (3) ◽

pp. 333-355 ◽

Cited By ~ 7

Author(s):

Chris Ugbode ◽

Yuhan Hu ◽

Benjamin Whalley ◽

Chris Peers ◽

Marcus Rattray ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Neurological Diseases ◽

Current Evidence ◽

Specific Targeting ◽

Disease Modifying Therapies ◽

The Central Nervous System ◽

Disease Modifying ◽

And Function

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Functions of the Alzheimer’s Disease Protease BACE1 at the Synapse in the Central Nervous System

Journal of Molecular Neuroscience ◽

10.1007/s12031-016-0800-1 ◽

2016 ◽

Vol 60 (3) ◽

pp. 305-315 ◽

Cited By ~ 20

Author(s):

Kathryn M. Munro ◽

Amelia Nash ◽

Martina Pigoni ◽

Stefan F. Lichtenthaler ◽

Jenny M. Gunnersen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Central Nervous System ◽

Nervous System ◽

The Central Nervous System

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Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice

Experimental Biology and Medicine ◽

10.1177/15353702211056866 ◽

2021 ◽

pp. 153537022110568

Author(s):

Natalia V Bobkova ◽

Daria Y Zhdanova ◽

Natalia V Belosludtseva ◽

Nikita V Penkov ◽

Galina D Mironova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Spatial Memory ◽

Intranasal Administration ◽

Brain Structures ◽

Brain Regions ◽

Dependent Manner ◽

Behavioral Experiments ◽

Hippocampal Cell Culture ◽

The Brain

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer’s type degeneration. Control OBX mice demonstrated loss of spatial memory tested in the Morris water maze. Immunocytochemical analysis revealed that allogeneic mitochondria colocalized with the markers of astrocytes and neurons in hippocampal cell culture. The results suggest that a non-invasive route intranasal administration of mitochondria may be a promising approach to the treatment of neurodegenerative diseases characterized, like Alzheimer's disease, by mitochondrial dysfunction.

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Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽

10.3390/cells10113261 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3261

Author(s):

Xiao Liu ◽

Qian Zhou ◽

Jia-He Zhang ◽

Xiaoying Wang ◽

Xiumei Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Disease Model ◽

Amyloid Β ◽

Brain Lesions ◽

Synaptic Dysfunction ◽

Synaptic Loss ◽

And Function ◽

The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

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Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

Brain Sciences ◽

10.3390/brainsci8090163 ◽

2018 ◽

Vol 8 (9) ◽

pp. 163 ◽

Cited By ~ 17

Author(s):

Caroline Gurvich ◽

Kate Hoy ◽

Natalie Thomas ◽

Jayashri Kulkarni

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Differences ◽

Cognitive Functioning ◽

Sex Hormones ◽

Reproductive Function ◽

Health And Disease ◽

And Function ◽

The Brain

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided.

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