Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration

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

Complement in neuroinflammation: Studies in leprosy and Amyotrophic Lateral Sclerosis

The complement system is a part of the innate immunity, and plays an important role in host immunity and inflammation. We previously identified the terminal membrane attack complex (MAC) of the complement system as a key determinant of neurodegeneration and demonstrated that its inhibition is neuroprotective. Besides being part of a mechanism of defence to invading pathogens, MAC has the capacity to cause damage to self-cells and is consequently implicated in many diseases. I describe studies on two diseases, Amyotrophic lateral sclerosis (ALS) and leprosy, both with severe impact on the nervous system. ALS is a progressive neurodegenerative disease, leading to muscle atrophy and eventually death. Leprosy is a chronic debilitating disease caused by Mycobacterium leprae (M. leprae), resulting in peripheral nerve impairment. The mechanisms of neurodegeneration in ALS and the molecular events of nerve injury due to M. leprae are unclear. However, in both diseases complement activation has been detected. I propose that complement activation, consequently MAC deposition on tissue, contributes to neurodegeneration and disease severity in Amyotrophic lateral sclerosis and leprosy. In this thesis I show that MAC targets the axons in nerve biopsies of leprosy patients and is deposited on at the neuromuscular-junction in muscle biopsies of ALS patients. In animal models I show that preventing MAC formation has an effect on demyelination in a model for M. leprae induced nerve damage, and also on the disease severity in a SODG93A mouse model of ALS. Overall, these experiments show that complement components are putative targets for future therapies

Dimensional transmutation in quantum theory

This work deals with two models - from the quantum eld theory it is the massless scalar electrodynamics (the so-called Coleman-Weinberg model) and from quantum mechanics it is the contact (-function) potential (in two dimensions) - that are apparently invariant under some sort of scale transformations and thus they, in suitably chosen units, contain only dimensionless parameters. It turns out that even in the quantum-mechanical case one has to add an additional procedure to the formal denition of the model and that the use of dierent physical regulators leads to the same results, that furthermore agree with the predictions of the mathematically rigorous method of self-adjoint operator extensions. In this work, we present detailed calculations supporting this result. Contrary to the common literature, we do so in a straightforward manner, which can be followed step by step (with all the necessary elements of functional analysis summarised in the Appendix). In quantum eld theory we apply a similar approach, when we "rediscover" the results of the abstract functional methods in the ordinary perturbation theory. In its framework, we further show how to obtain predictions also for other quantities than particle masses

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin.

Mycobacterium leprae (M. leprae) infection causes nerve damage and the condition worsens often during and long after treatment. Clearance of bacterial antigens including lipoarabinomannan (LAM) during and after treatment in leprosy patients is slow. We previously demonstrated that M. leprae LAM damages peripheral nerves by in situ generation of the membrane attack complex (MAC). Investigating the role of complement activation in skin lesions of leprosy patients might provide insight into the dynamics of in situ immune reactivity and the destructive pathology of M. leprae. In this study, we analyzed in skin lesions of leprosy patients, whether M. leprae antigen LAM deposition correlates with the deposition of complement activation products MAC and C3d on nerves and cells in the surrounding tissue. Skin biopsies of paucibacillary (n = 7), multibacillary leprosy patients (n = 7), and patients with erythema nodosum leprosum (ENL) (n = 6) or reversal reaction (RR) (n = 4) and controls (n = 5) were analyzed. The percentage of C3d, MAC and LAM deposition was significantly higher in the skin biopsies of multibacillary compared to paucibacillary patients (p = <0.05, p = <0.001 and p = <0.001 respectively), with a significant association between LAM and C3d or MAC in the skin biopsies of leprosy patients (r = 0.9578, p< 0.0001 and r = 0.8585, p<0.0001 respectively). In skin lesions of multibacillary patients, MAC deposition was found on axons and co-localizing with LAM. In skin lesions of paucibacillary patients, we found C3d positive T-cells in and surrounding granulomas, but hardly any MAC deposition. In addition, MAC immunoreactivity was increased in both ENL and RR skin lesions compared to non-reactional leprosy patients (p = <0.01 and p = <0.01 respectively). The present findings demonstrate that complement is deposited in skin lesions of leprosy patients, suggesting that inflammation driven by complement activation might contribute to nerve damage in the lesions of these patients. This should be regarded as an important factor in M. leprae nerve damage pathology

Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis

Complement activation products are elevated in cerebrospinal fluid, spinal cord and motor cortex of patients with amyotrophic lateral sclerosis (ALS) but are untested in models. We determined complement expression and activation in the SOD1 G93A mouse model of familial ALS (fALS). At 126 days, C3 mRNA was upregulated in spinal cord and C3 protein accumulated in astrocytes and motor neurons. C3 activation products C3b/iC3b were localized exclusively on motor neurons. At the neuromuscular junction, deposits of C3b/iC3b and C1q were detected at day 47, before the appearance of clinical symptoms, and remained detectable at symptomatic stage (126 days). Our findings implicate complement in the denervation of the muscle endplate by day 47 and destruction of the neuromuscular junction and spinal neuron loss by day 126 in the SOD1 G93A mouse model of fALS

Additional file 4: Figure S4. of Complement activation at the motor end-plates in amyotrophic lateral sclerosis

Representative confocal immunofluorescence for synaptophysin (SYN-Cy3) detecting the motor nerve terminal (A, B) or S100b (Cy3) detecting the terminal Schwann cells (C, D) double stained with anti-CD55 (FITC) in control (A, C) and ALS (B, D) intercostal muscle shows CD55 co-localizing with both synaptophysin and S100b (white arrow in B and D, respectively) but no CD55 deposition in controls. (TIF 1271 kb

Additional file 1: Figure S1. of Complement activation at the motor end-plates in amyotrophic lateral sclerosis

Representative confocal immunofluorescence for synaptophysin (SYN-Cy3) detecting the motor nerve terminal (A, B) or S100b (Cy3) detecting the terminal Schwann cells (C, D) double stained with anti-C1q (FITC) in control (A, C) and ALS (B, D) intercostal muscle shows C1q co-localizing with both synaptophysin and S100b (white arrow in B and D, respectively) but no C1q deposition in controls. (TIF 1461 kb