Synaptic Loss and Neurodegeneration

Editorial

21 April 2021

Editorial: Synaptic Loss and Neurodegeneration

Jaichandar Subramanian

and

Marie-Ève Tremblay

5,491 views

8 citations

Editors

Marie-Ève Tremblay

University of Victoria

Jaichandar (Jai) Subramanian

University of Kansas

Impact

Review

21 December 2020

Synaptic Loss in Alzheimer's Disease: Mechanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models

Jaichandar Subramanian

, 1 more and

Marie-Ève Tremblay

Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.

18,718 views

83 citations

Male (left); female (right); saline (black outlined white bars with black outlined circles); poly I:C (black bars with black outline squares). n = 4–5 animals per group. *p < 0.05, **p < 0.01. mIA led to decreased expression of C1q and C3 in the hippocampus, reduced levels of C1q and increased levels of C3 in the DG in a sex independent manner, while increasing CD11b levels in the DG of female offspring. (A) Relative expression of C1q in the DG. There was an overall reduction from maternal poly I:C exposure [F(1, 15) = 5.19, p = 0.04]. There was not an overall effect of sex [F(1, 15) = 0.65, p = 0.43] or interaction between the two factors [F(1, 15) = 2.70, p = 0.12]. (B) Relative expression of C3 in the DG. As with C1q, there was an overall reduction in offspring whose dams were exposed to poly I:C [F(1, 14) = 7.16, p = 0.02]. There was not an effect of sex [F(1, 14) = 0.06, p = 0.81] or an interaction between the two [F(1, 14) = 0.25, p = 0.63]. (C) C1q levels were lower in offspring whose dams were exposed to poly I:C [F(1, 15) = 4.89, p = 0.04]. There was not an overall effect of sex [F(1, 15) = 0.009, p = 0.93] or interaction between the two [F(1, 15) = 1.81, p = 0.20]. (D) Representative images (left half: males, right half: females; saline: top, poly I:C: bottom) of C1q levels in the hippocampal DG (MAP2 (neurons; red, left); C1q (green, middle); merged [MAP2 (red)/C1q (green)/DAPI stained nuclei (blue); right)]. Each image was from the DG and includes the granule cell layer (GL) and polymorphic layer (PL). Scale bar = 50 μm. (E) Representative images (left half: males, right half: females; saline: top, poly I:C: bottom) of C3 levels in the DG [GFAP (astrocytes; red, left); C3 (green, middle); merged (GFAP (red)/C3 (green)/DAPI stained nuclei (blue); right)]. Each image was from the DG and includes the GL and PL. Scale bar = 50 μm. (F) C3 levels were greater in offspring from poly I:C exposed mothers [F(1, 13) = 10.01, p = 0.008]. There was not an effect of sex [F(1, 13) = 0.008, p = 0.93] or an interaction between the two [F(1, 13) = 0.04, p = 0.84]. (G) GFAP levels were also greater in offspring following maternal poly I:C administration [F(1, 13) = 14.65, p = 0.002]. There was not an effect of sex [F(1, 13) = 2.37, p = 0.15] or interaction between the two [F(1, 13) = 0.33, p = 0.57]. (F) The levels of C3 in GFAP+ positive cells was also greater in offspring when dams were exposed to poly I:C [F(1, 13) = 9.65, p = 0.008]. There was not an effect of sex [F(1, 13) = 0.31, p = 0.59] or an interaction between the two [F(1, 13) = 0.04, p = 0.84]. (H) Representative images of CD11b (green) levels in the DG (left: males, right half: females; saline: top, poly I:C: bottom). Each image was from the DG and includes the GL and PL. Scale bar = 50 μm. (I) CD11b levels were greater in offspring following maternal poly I:C administration [F(1, 15) = 4.61, p = 0.05]; furthermore, female offspring, from dams who were exposed to either saline or poly I:C had greater CD11b levels [F(1, 15) = 11.57, p = 0.004]. There was not an interaction between the two [F(1, 15) = 1.34, p = 0.26].

Brief Research Report

15 October 2020

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

Chin Wai Hui

, 8 more and

Marie-Ève Tremblay

9,871 views

45 citations

Review

04 October 2019

Role of Exosomes in Central Nervous System Diseases

Wanying Liu

, 4 more and

Junping Zhang

There are many types of intercellular communication, and extracellular vesicles are one of the important forms of this. They are released by a variety of cell types, are heterogeneous, and can roughly be divided into microvesicles and exosomes according to their occurrence and function. Of course, exosomes do not just play a role in cell-to-cell communication. In the nervous system, exosomes can participate in intercellular communication, maintain the myelin sheath, and eliminate waste. Similarly, exosomes in the brain can play a role in central nervous system diseases, such as stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), prion disease, and traumatic encephalopathy (CTE), with both positive and negative effects (such as the transfer of misfolded proteins). Exosomes contain a variety of key bioactive substances and can therefore be considered as a snapshot of the intracellular environment. Studies have shown that exosomes from the central nervous system can be found in cerebrospinal fluid and peripheral body fluids, and that their contents will change with disease occurrence. Because exosomes can penetrate the blood brain barrier (BBB) and are highly stable in peripheral circulation, they can protect disease-related molecules well and therefore, using exosomes as a biomarker of central nervous system diseases is an attractive prospect as they can be used to monitor disease development and enable early diagnosis and treatment optimization. In this review, we discuss the current state of knowledge of exosomes, and introduce their pathophysiological roles in different diseases of the central nervous system as well as their roles and applications as a viable pathological biomarker.

22,469 views

193 citations

Neuron-specific knockdown of Cytochrome C Oxidase subunit 4 (Cox4). (A) Determination of lentiviral transduction efficiency, i.e., percentage of cells positive for both virally expressed EGFP and neuronal marker Microtubule-associated protein 2 (MAP2). Micrographs depict confocal images of a rat primary neuronal culture transduced with Lenti04CmiCox79/SEW (miCox79) and counterstained for MAP2. n = 10 images for all groups. (B,C) Knockdown of rat Cox4 expression as assessed by quantitative real-time PCR (B) and single-cell quantitative immunocytochemistry (C) in lentivirally transduced primary rat neurons in vitro. One-way ANOVA, Dunnett’s multiple comparisons test. ***p < 0.001; **p < 0.01. n = 6 wells for all groups (B). Kruskal–Wallis test, Dunn’s multiple comparisons test. ***p < 0.001; **p < 0.01. n = 25 cells for all groups (C). (D,E) Determination of cell viability and activated caspase 3/7 (ApoLive-GloTM Multiplex Assay) in cultures of rat primary neurons after lentiviral transduction with either miCTR, miCox79 or miCox474 expressing lentiviral vectors. One-way ANOVA, Dunnett’s multiple comparisons test. n.s., not significant. n = 6 wells for all groups. (F) Determination of ATP content in primary rat neurons transduced with miCTR or miCox79 expressing lentiviral vectors and treated with picomolar concentrations of rotenone for 30 min before measurement. Multiple t-tests. ***p < 0.001; **p < 0.01. n = 6 wells for all groups.

Original Research

24 March 2020

Interference With Complex IV as a Model of Age-Related Decline in Synaptic Connectivity

Martin Kriebel

, 3 more and

Hansjürgen Volkmer

4,972 views

14 citations

Review

13 August 2019

The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis

Jonu Pradhan

, 1 more and

Mark C. Bellingham

Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A₂_aRs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A₂_aRs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A₂_aRs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A₂_aRs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A₂_aRs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.

29,650 views

108 citations

Association of lipopolysaccharide (LPS) with human neuronal-glial (HNG) cells in primary co-culture; (A) HNG cells are a primary co-culture of neuronal [β-tubulin III (βTUBIII)-stained; red; λmax = 690 nm] and glial (GFAP-stained; green; λmax = 520 nm) human brain cells; cells are also stained for nuclei (DAPI-stained; blue; λmax = 470 nm); cells shown are ∼2 weeks in culture; HNG cells are ∼60% neurons and ∼40% astroglia at ∼65% confluency; human primary neuronal and glial “support” cell co-cultures are utilized, because human neuronal cells do not culture well by themselves (Cui et al., 2010; Zhao et al., 2017b); HNG cells are electrically active and extremely sensitive to pro-inflammatory neurotoxins in the nM range (Lonza human cell systems; transplantation grade; Zhao et al., 2017b); yellow bar ∼20 um; HNG cells were exposed to 50 nM LPS for 36 h; (B) LPS (red; λmax = 690 nm) and nuclei (blue; λmax = 470 nm) stained HNG cells; four white arrows indicate perinuclear clustering of LPS as has been previously reported (Hill and Lukiw, 2015; Zhan et al., 2016, 2018; Yang and Chiu, 2017; Zhao et al., 2017a,c); panels (C–F) show details of LPS-neuronal cell interactions in a single neuron; LPS preferentially associates with neuronal nuclei and non-neuronal nuclei to a lesser extent (Zhao et al., 2017a,b,c; Zhao and Lukiw, 2018a,b); (C) β-TUBIII (green stain, λmax = 520 nm) is a neuron-specific stain; a single neuron is highlighted; (D) LPS (red stain; λmax = 690 nm) shows non-homogeneous clustering of LPS stain; (E) LPS (red stain; λmax = 690 nm) and DAPI-stained nuclei (blue stain; λmax = 470 nm) shows a “polarized” LPS affinity for the periphery of neuronal nuclei (see Zhao et al., 2017c); (F) merge of all signals; all yellow bars in (A–F) ∼20 um; LPS attraction for neuronal nuclei may be in part glial-cell modulated; there is recent evidence that perinuclear LPS may disrupt the normal transcriptional output of human neuronal nuclei for neuron-specific components such as the neurofilament light chain (NF-L) protein (Lukiw et al., 2018; Zhao et al., 2019).

Perspective

10 July 2019

Down-Regulation of Essential Synaptic Components by GI-Tract Microbiome-Derived Lipopolysaccharide (LPS) in LPS-Treated Human Neuronal-Glial (HNG) Cells in Primary Culture: Relevance to Alzheimer’s Disease (AD)

Yuhai Zhao

, 2 more and

Walter J. Lukiw

4,897 views

23 citations

Hypothetical HCN channel-related pathogenic cascade in SNc dopaminergic neurons in PD. (A) HCN channels modulate the electrophysiological activities of SNc dopaminergic neurons. Dopaminergic neurons display tonic irregular single-spike firing and phasic burst firing in vivo, and slow, regular, pacemaker activity in vitro. HCN channels blockade with ZD7288 reduces the amplitude of Ih, leading to cell membrane hyperpolarization, decreased firing activity, or even increased burst firing in vitro. HCN channels also regulate neuronal oscillatory activity. (B) Proposed mechanism for the involvement of HCN channels in the neurotoxic effects of MPP+. MPP+ accumulates in mitochondria, where it inhibits complex I, causing ATP depletion, increased ROS formation, and oxidative stress. The decreased cellular ATP and cAMP concentration leads to the opening of K-ATP channels and inhibition of HCN channels. This results in hyperpolarization of the cell membrane and reduction in the spontaneous firing of dopaminergic neurons. MPP+ is also speculated to directly interact with HCN channels, causing Ih inhibition. This further leads to the amplification of SCRs by potentiating EPSP and depressing IPSP, which results in an imbalance of intracellular calcium homeostasis. This in turn potentiates oxidative stress and ultimately leads to cell death.

Review

05 June 2019

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases

Xiaoli Chang

, 3 more and

Junxia Xie

21,520 views

60 citations

Smn missense mutations or knockdown reduce larval locomotion. (A) Larval crawling speed, measured in body lengths/s, in early third instar larvae. (B) Representative traces for the data shown in (A). (C) Larval size for the same animals measured in the locomotion assay in (A). (D) Larval crawling speed, measured in body lengths per second, in wandering third instar larvae. (E) Representative traces for the data shown in (D). (F) Larval size for the same animals measured in the locomotion assay in (D). Data: bars show averages, points represent individual larvae, error bars represent standard error, n-values (# individual larvae) are shown in parentheses adjacent to genotype on x-axis. Statistical significance was determined by ANOVA (ns = not significant, *p < 0.05, **p < 0.01, ***p < 0.001).

Original Research

16 May 2019

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Ashlyn M. Spring

, 3 more and

A. Gregory Matera

4,833 views

49 citations

Pathophysiology of Alzheimer’s disease (AD). The build-up of pathological amyloid and tau species leads to neurodegeneration via numerous autonomous and non-autonomous pathways. Glial cells release pro-inflammatory mediators and lose their ability to regulate glutamate homeostasis, leading to synaptic dysfunction. Furthermore, the synaptic accumulation of proteins from the complement system leads to glial-dependent synapse engulfment and loss.

Review

26 February 2019

Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration

Christopher M. Henstridge

, 1 more and

Rosa C. Paolicelli

Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling.

26,964 views

116 citations