Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells

We have investigated the effects of Chlamydia pneumoniae on human brain endothelial cells (HBMECs) and human monocytes as a mechanism for breaching the blood-brain barrier (BBB) in Alzheimer's disease (AD). HBMECs and peripheral blood monocytes may be key components in controlling the entry of C. pneumoniae into the human brain. Our results indicate that C. pneumoniae infects blood vessels and monocytes in AD brain tissues compared with normal brain tissue. C. pneumoniae infection stimulates transendothelial entry of monocytes through HBMECs. This entry is facilitated by the up-regulation of VCAM-1 and ICAM-1 on HBMECs and a corresponding increase of LFA-1, VLA-4, and MAC-1 on monocytes. C. pneumoniae infection in HBMECs and THP-1 monocytes up-regulates monocyte transmigration threefold in an in vitro brain endothelial monolayer. In this way, C. pneumoniae infection in these cell types may contribute to increased monocyte migration and promote inflammation within the CNS resulting from infection at the level of the vasculature. Thus, infection at the level of the vasculature may be a key initiating factor in the pathogenesis of neurodegenerative diseases such as sporadic AD.     

Role of astroglial toll-like receptors (TLRs) in central nervous system infections,injury and neurodegenerative diseases

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response. Toll-like receptors (TLRs) are a well-characterized family of PRRs. The contribution of microglial TLR signaling to CNS pathology has been extensively investigated. Even though astrocytes assume a wide variety of key functions, information about the role of astroglial TLRs in CNS disease and injuries is limited. Because astrocytes display heterogeneity and exhibit phenotypic plasticity depending on the effectors present in the local milieu, they can exert both detrimental and beneficial effects. TLRs are modulators of these paradoxical astroglial properties. The goal of the current review is to highlight the essential roles played by astroglial TLRs in CNS infections, injuries and diseases. We discuss the contribution of astroglial TLRs to host defense as well as the dissemination of viral and bacterial infections in the CNS. We examine the link between astroglial TLRs and the pathogenesis of neurodegenerative diseases and present evidence showing the pivotal influence of astroglial TLR signaling on sterile inflammation in CNS injury. Finally, we define the research questions and areas that warrant further investigations in the context of astrocytes, TLRs, and CNS dysfunction.     

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death‐1 (PD1) checkpoint inhibition produces an IFN‐γ‐dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., ( 2016 ): Nature Medicine, 22:135–137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid‐β pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti‐PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte‐derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., ( 2016 ): Nature Medicine, 22:135–137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.     

Stem cell challenges in the treatment of neurodegenerative disease

Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases.     

Review: Somatic mutations in neurodegeneration

Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.     

Dopamine: an immune transmitter

The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson's disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson's disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.     

Zebrafish as a model for investigating developmental lead (Pb) neurotoxicity as a risk factor in adult neurodegenerative disease: A mini-review

Lead (Pb) exposure has long been recognized to cause neurological alterations in both adults and children. While most of the studies in adults are related to higher dose exposure, epidemiological studies indicate cognitive decline and neurobehavioral alterations in children associated with lower dose environmental Pb exposure (a blood Pb level of 10 μg/dL and below). Recent animal studies also now report that an early-life Pb exposure results in pathological hallmarks of Alzheimer's disease later in life. While previous studies evaluating higher Pb exposures in adult animal models and higher occupational Pb exposures in humans have suggested a link between higher dose Pb exposure during adulthood and neurodegenerative disease, these newer studies now indicate a link between an early-life Pb exposure and adult neurodegenerative disease. These studies are supporting the “fetal/developmental origin of adult disease” hypothesis and present a new challenge in our understanding of Pb neurotoxicity. There is a need to expand research in this area and additional model systems are needed. The zebrafish presents as a complementary vertebrate model system with numerous strengths including high genetic homology. Several zebrafish genes orthologous to human genes associated with neurodegenerative diseases including Alzheimer's and Parkinson's diseases are identified and this model is starting to be applied in neurodegenerative disease research. Moreover, the zebrafish is being used in developmental Pb neurotoxicity studies to define genetic mechanisms of toxicity and associated neurobehavioral alterations. While these studies are in their infancy, the genetic and functional conservation of genes associated with neurodegenerative diseases and application in developmental Pb neurotoxicity studies supports the potential for this in vivo model to further investigate the link between developmental Pb exposure and adult neurodegenerative disease pathogenesis. In this review, the major factors influencing the pathogenesis of neurodegenerative diseases, Pb neurotoxicity, the developmental origin of adult disease paradigm, and the zebrafish as a model system to investigate the developmental origin of low-dose Pb-induced neurodegenerative diseases is discussed.     

Immunology meets neuroscience--opportunities for immune intervention in neurodegenerative diseases

Neuroinflammatory changes are characteristic of many, if not all, neurodegenerative diseases but the extent to which the immune system is involved in the pathogenesis of these diseases is unclear. The findings of several studies during the past decade has established that there is a well-developed communication between the central nervous system (CNS) and the peripheral immune system, but also has revealed that the immune system in the CNS is much more sophisticated that previously acknowledged. In this mini-review, we discuss two major neurodegenerative disorders, Alzheimer’s disease (AD) and multiple sclerosis (MS), and consider whether the therapies most likely to succeed are those that are identified by studying the marriage of neuroscience and immunology.     

Mounting evidence of FKBP12 implication in neurodegeneration

Intrinsically disordered proteins, such as tau or α-synuclein, have long been associated with a dysfunctional role in neurodegenerative diseases. In Alzheimer's and Parkinson's' diseases, these proteins, sharing a common chemical-physical pattern with alternating hydrophobic and hydrophilic domains rich in prolines, abnormally aggregate in tangles in the brain leading to progressive loss of neurons. In this review, we present an overview linking the studies on the implication of the peptidyl-prolyl isomerase domain of immunophilins, and notably FKBP12, to a variety of neurodegenerative diseases, focusing on the molecular origin of such a role. The involvement of FKBP12 dysregulation in the aberrant aggregation of disordered proteins pinpoints this protein as a possible therapeutic target and, at the same time, as a predictive biomarker for early diagnosis in neurodegeneration, calling for the development of reliable, fast and cost-effective detection methods in body fluids for community-based screening campaigns.     

CD11a expression distinguishes infiltrating myeloid cells from plaque-associated microglia in Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of age-related neurodegeneration and is characterized neuropathologically by the accumulation of insoluble beta-amyloid (Aβ) peptides. In AD brains, plaque-associated myeloid (PAM) cells cluster around Aβ plaques but fail to effectively clear Aβ by phagocytosis. PAM cells were originally thought to be brain-resident microglia. However, several studies have also suggested that Aβ-induced inflammation causes peripheral monocytes to enter the otherwise immune-privileged brain. The relationship between AD progression and inflammation in the brain remains ambiguous because microglia and monocyte-derived macrophages are extremely difficult to distinguish from one another in an inflamed brain. Whether PAM cells are microglia, peripheral macrophages, or a mixture of both remains unclear. CD11a is a component of the β2 integrin LFA1. We have determined that CD11a is highly expressed on peripheral immune cells, including macrophages, but is not expressed by mouse microglia. These expression patterns remain consistent in LPS-treated inflamed mice, as well as in two mouse models of AD. Thus, CD11a can be used as a marker to distinguish murine microglia from infiltrating peripheral immune cells. Using CD11a, we show that PAM cells in AD transgenic brains are comprised entirely of microglia. We also demonstrate a novel fluorescence-assisted quantification technique (FAQT), which reveals a significant increase in T lymphocytes, especially in the brains of female AD mice. Our findings support the notion that microglia are the lead myeloid players in AD and that rejuvenating their phagocytic potential may be an important therapeutic strategy.     

Therapeutic role of inflammasome inhibitors in neurodegenerative disorders

Neuroinflammation, characterized by the activation of glial cells, is a hallmark in several neurological and neurodegenerative disorders. Inadequate inflammation cannot eliminate the infection of pathogens, while excessive or hyper-reactive inflammation can cause chronic or systemic inflammatory diseases affecting the central nervous system (CNS). In response to a brain injury or pathogen invasion, the pathogen recognition receptors (PRRs) expressed on glial cells are activated via binding to cellular damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). This subsequently leads to the activation of NOD (nucleotide-binding oligomerization domain)-like receptor proteins (NLRs). In neurodegenerative diseases such as HIV-1-associated neurocognitive disorders (HAND), Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), chronic inflammation is a critical contributing factor for disease manifestation including pathogenesis. Emerging evidence points to the involvement of “inflammasomes”, especially the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) complex in the development of these diseases. The activated NLRP3 results in the proteolytic activation of caspase-1 that facilitates the cleavage of pro-IL-1β and the secretion of IL-1β and IL-18 proinflammatory cytokines. Accordingly, these and other seminal findings have led to the development of NLRP-targeting small-molecule therapeutics as possible treatment options for neurodegenerative disorders. In this review, we will discuss the new advances and evidence-based literature concerning the role of inflammasomes in neurodegenerative diseases, its role in the neurological repercussions of CNS chronic infection, and the examples of preclinical or clinically tested NLRP inhibitors as potential strategies for the treatment of chronic neurological diseases.     

Copper handling by astrocytes: insights into neurodegenerative diseases

Copper (Cu) is an essential trace element in the brain that can be toxic at elevated levels. Cu accumulation is a suspected etiology in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and prion-induced disorders. Astrocytes are a proposed depot in the brain for Cu and other metals, including lead (Pb). This article describes the physiological roles of Cu in the central nervous system and in selected neurodegenerative diseases, and reviews evidence that astrocytes accumulate Cu and protect neurons from Cu toxicity. Findings from murine genetic models of Menkes disease and from cell culture models concerning the molecular mechanisms by which astrocytes take up, store, and buffer Cu intracellularly are discussed, as well as potential mechanistic linkages between astrocyte functions in Cu handling and neurodegenerative diseases.     

Changes in matrix metalloprotease activity and progranulin levels may contribute to the pathophysiological function of mutant leucine‐rich repeat kinase 2

Increasing evidence suggests that Parkinson's disease (PD)‐linked Leucine‐rich repeat kinase 2 (LRRK2) has a role in peripheral and brain‐resident immune cells. Furthermore, dysregulation of the anti‐inflammatory, neurotrophic protein progranulin (PGRN) has been demonstrated in several chronic neurodegenerative diseases. Here we show that PGRN levels are significantly reduced in conditioned medium of LRRK2(R1441G) mutant mouse fibroblasts, leukocytes, and microglia, whereas levels of proinflammatory factors, like interleukin‐1β and keratinocyte‐derived chemokine, were significantly increased. Decreased PGRN levels were also detected in supernatants of cultured human fibroblasts isolated from presymptomatic LRRK2(G2019S) mutation carriers, while mitochondrial function was unaffected. Furthermore, medium levels of matrix metalloprotease (MMP) 2 increased, whereas MMP 9 decreased in LRRK2(R1441G) mutant microglia. Increased proteolytic cleavage of the MMP substrates ICAM‐5 and α‐synuclein in synaptoneurosomes from LRRK2(R1441G) mutant mouse brain indicates increased net synaptic MMP activity. PGRN levels were decreased in the cerebrospinal fluid of presymptomatic LRRK2 mutant mice, whereas PGRN levels were increased in aged symptomatic mutant mice. Notably, PGRN levels were also increased in the cerebrospinal fluid of PD patients carrying LRRK2 mutations, but not in idiopathic PD patients and in healthy control donors. Our data suggest that proinflammatory activity of peripheral and brain‐resident immune cells may particularly contribute to the early stages of Parkinson's disease caused by LRRK2 mutations. GLIA 2014;62:1075–1092     

Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson's Disease

Neuroinflammatory processes play a significant role in the pathogenesis of Parkinson’s disease (PD). Epidemiologic, animal, human, and therapeutic studies all support the presence of a neuroinflammatory cascade in disease. This is highlighted by the neurotoxic potential of microglia. In steady-state, microglia serve to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of innate and adaptive immune responses. In neurodegenerative diseases, activated microglia affect neuronal injury and death through production of glutamate, pro-inflammatory factors, reactive oxygen species, quinolinic acid among others and by mobilization of adaptive immune responses and cell chemotaxis leading to transendothelial migration of immunocytes across the blood–brain barrier and perpetuation of neural damage. As disease progresses, inflammatory secretions engage neighboring glial cells, including astrocytes and endothelial cells, resulting in a vicious cycle of autocrine and paracrine amplification of inflammation perpetuating tissue injury. Such pathogenic processes contribute to neurodegeneration in PD. Research from others and our own laboratories seek to harness such inflammatory processes with the singular goal of developing therapeutic interventions that positively affect the tempo and progression of human disease.     

Elevated CNS inflammation in patients with preclinical Alzheimer's disease

Alzheimer''s disease (AD) is a progressive, neurodegenerative disease that may involve inflammatory responses in the central nervous system (CNS). Our objective was to determine whether patients with amnestic mild cognitive impairment (aMCI), a preclinical stage of AD, have inflammatory characteristics similar to patients with multiple sclerosis (MS), a known CNS inflammatory disease. The frequency of lymphocytes and levels of pro-inflammatory cytokines in the cerebrospinal fluid of aMCI patients was comparable to MS patients or patients at high risk to develop MS. Thus, brain inflammation occurs early at the preclinical stage of AD and may have an important role in pathology.     

Neural stem cell‐based treatment for neurodegenerative diseases

Human neurodegenrative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell‐based cell therapies for neurodegenerative diseases have been developed. A recent advance in generatioin of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenrative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell‐mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury.     

Microglial cells in neurodegenerative disorders

Microglia are resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. It is widely accepted that microglia contribute to the neurodegeneration through a release of a variety of proinflammatory substances. In fact, they are not the only cells which contribute to immunological processes inside the nervous system. The CNS is composed of different cell populations that answer to pathological factors and influence each other and modulate their reactions. These complex interactions are responsible for the development of brain pathology. This paper reviews the available information on microglial cells contribution to AD, PD and prion diseases development.     

The effect of drug treatment on neurogenesis in Parkinson's disease

There has been recent interest in the possibility that impaired neurogenesis may contribute to the decline in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). We have investigated the effects of commonly used treatments for PD on neural stem cell (NSC) activity in nondemented patients. Postmortem of brain tissue containing the subventricular zone (SVZ) and ependymal layer cells was obtained from 32 nondemented patients with PD. NSC activity was assessed by immunohistochemical staining for RNA‐binding protein Musashi1. Regression analyses were then used to identify which clinical factors independently influenced NSC activity. Disease duration was negatively associated with SVZ Musashi1 staining, whereas lifetime levodopa was positively associated in this region. Our findings suggest a positive impact of chronic L ‐dopa use on the number of NSC in the SVZ of PD patients, which may have relevance for future studies on neuroprotection in neurodegenerative diseases. © 2010 Movement Disorder Society.     

Regulated upon activation,normal T cell expressed and secreted (RANTES) levels in the peripheral blood of patients with Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia, but it is very difficult to diagnose with certainty, so many AD studies have attempted to find early and relevant diagnostic markers. Regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand) is a chemokine involved in the migration of T cells and other lymphoid cells. Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases, such as Parkinson’s disease and multiple sclerosis, but also in metabolic diseases in which inflammation plays a role. The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD. Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD (median 8.5 months after diagnosis; 39 men and 46 women; average age 75.7 years), and in 78 control subjects (24 men and 54 women; average age 66 years). We found much higher plasma levels of RANTES in AD patients compared to controls. A negative correlation of RANTES levels with age, disease duration, Fazekas scale score, and the medial temporal lobe atrophy (MTA) score (Scheltens’s scale) was found in AD patients, i.e., the higher levels corresponded to earlier stages of the disease. Plasma RANTES levels were not correlated with cognitive scores. In AD patients, RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which is consistent with the well-known fact that AD is associated with inflammatory processes. RANTES levels were also positively correlated with insulin levels in AD patients, with insulin resistance (HOMA-R) and pancreatic beta cell function (HOMA-F). This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES, but these factors could not explain the increases in RANTES levels observed in AD patients. Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD. The study was approved by the Ethics Committee of Institute of Endocrinology, Prague, Czech Republic on July 22, 2011.