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Cholinergic imbalance in the multiple sclerosis hippocampus

Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this diseas

Cortical remyelination is heterogeneous in multiple sclerosis

Cortical lesions (CLs) are an important component of multiple sclerosis (MS) pathology; they correlate better with physical disability and cognitive impairment than white matter lesions (WMLs). Because remyelination can be extensive in CLs, we quantified remyelination in gray matter (GM) and white matter (WM), addressing oligodendrocyte (OGD) maturation state and clinical relevance of remyelination. Brain tissue samples from 21 chronic MS patients were immunohistochemically stained for myelin proteolipid protein, Olig2, which is strongly expressed in OGD precursor cells (OPCs), but weakly expressed in mature OGDs and other OGD markers. Sections were scored for the presence of normal-appearing WM and GM, de- and remyelination, and OPC and OGD cell counts. Remyelination was significantly more extensive in CLs than in WMLs with a trend toward more GM remyelination in primary progressive MS (PPMS) vs relapse-onset MS patients. More OPCs were found in remyelinated and nonremyelinated CLs vs remyelinated WMLs and nonremyelinated WMLs. Thus, there is more remyelination in the GM than in the WM in MS patient brains, with a trend toward more remyelination in those with PPMS. There does not seem to be a significant OPC recruitment failure in the GM, which casts new light on the process of remyelination failure

Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis

Microglial clusters with C3d deposits are observed in the periplaque of multiple sclerosis (MS) brains and were proposed as early stage of lesion formation. As such they should appear in the brain of MS donors with acute disease but thus far this has not been shown. Using postmortem brain tissue from acute (n = 10) and chronic (n = 15) MS cases we investigated whether C3d+ microglial clusters are part of an acute attack against myelinated axons, which could have implications for disease pathogenesis. The specificity of our findings to MS was tested in ischemic stroke cases (n = 8) with initial or advanced lesions and further analyzed in experimental traumatic brain injury (TBI, n = 26), as both conditions are primarily nondemyelinating but share essential features of neurodegeneration with MS lesions. C3d+ microglial clusters were found in chronic but not acute MS. They were not associated with antibody deposits or terminal complement activation. They were linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production. C3d+ microglial clusters were not specific to MS as they were also found in stroke and experimental TBI. We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons. As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease. GLIA 2017;65:264–277

Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, leading to memory impairment in up to 65% of patients. Memory dysfunction in MS has been associated with loss of synapses in the hippocampus, but its molecular basis is unknown. Accumulating evidence suggests that components of the complement system, C1q and C3, can mediate elimination of synapses. To investigate the involvement of complement in synaptic changes in MS, gene and protein expression and localization of C1q and C3 were analyzed in relation to neuropathological changes in myelinated and demyelinated hippocampi from postmortem MS brains. Findings were compared to hippocampi of Alzheimer disease (AD) and non-neurological controls. C1q expression and C3 activation were increased in myelinated and demyelinated MS hippocampi, mainly in the CA3/2 and CA1 subfields, which also showed a marked decrease in synaptic density and increased neuronal staining for the mitochondrial heat shock protein 70 (mtHSP70) stress marker. Neurons were the major source of C1q mRNA. C1q protein and activated C3 localized at synapses within human leukocyte antigen-positive cell processes and lysosomes, suggesting engulfment of complement-tagged synapses by microglia. A significant association (p  < 0.0001) between the density of C1q and synaptophysin-positive synapses or mtHSP70 was seen in myelinated MS hippocampi, further pointing toward a link between the complement pathway and synaptic changes. In contrast to AD, MS hippocampi were consistently negative for the terminal complement activation complex C5b9. These data support a role for the C1q-C3 complement axis in synaptic alterations in the MS hippocampu

B-Cell Depletion Attenuates White and Gray Matter Pathology in Marmoset Experimental Autoimmune Encephalomyelitis

This study investigated the effect of CD20-positive B-cell depletion on central nervous system (CNS) white and gray matter pathology in experimental autoimmune encephalomyelitis in common marmosets, a relevant preclinical model of multiple sclerosis. Experimental autoimmune encephalomyelitis was induced in 14 marmosets by immunization with recombinant human myelin oligodendrocyte glycoprotein in complete Freund adjuvant. At 21 days after immunization, B-cell depletion was achieved by weekly intravenous injections of HuMab 7D8, a human-anti-human CD20 antibody that cross-reacts with marmoset CD20. In vivo magnetic resonance imaging showed widespread brain white matter demyelination in control marmosets that was absent in CD20 antibody-treated marmosets. High-contrast post-mortem magnetic resonance imaging showed white matter lesions in 4 of the 7 antibody-treated marmosets, but these were significantly smaller than those in controls. The same technique revealed gray matter lesions in 5 control marmosets, but none in antibody-treated marmosets. Histologic analysis confirmed that inflammation, demyelination, and axonal damage were substantially reduced in brain, spinal cord, and optic nerves of CD20 antibody-treated marmosets. In conclusion, CD20-postive B-cell depletion by HuMab 7D8 profoundly reduced the development of both white and gray matter lesions in the marmoset CNS. These data underline the central role of B cells in CNS inflammatory-demyelinating disease

Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation

Abstract Background In brain tissues from multiple sclerosis (MS) patients, clusters of activated HLA-DR-expressing microglia, also referred to as preactive lesions, are located throughout the normal-appearing white matter. The aim of this study was to gain more insight into the frequency, distribution and cellular architecture of preactive lesions using a large cohort of well-characterized MS brain samples. Methods Here, we document the frequency of preactive lesions and their association with distinct white matter lesions in a cohort of 21 MS patients. Immunohistochemistry was used to gain further insight into the cellular and molecular composition of preactive lesions. Results Preactive lesions were observed in a majority of MS patients (67%) irrespective of disease duration, gender or subtype of disease. Microglial clusters were predominantly observed in the vicinity of active demyelinating lesions and are not associated with T cell infiltrates, axonal alterations, activated astrocytes or blood–brain barrier disruption. Microglia in preactive lesions consistently express interleukin-10 and TNF-α, but not interleukin-4, whereas matrix metalloproteases-2 and −9 are virtually absent in microglial nodules. Interestingly, key subunits of the free-radical-generating enzyme NADPH oxidase-2 were abundantly expressed in microglial clusters. Conclusions The high frequency of preactive lesions suggests that it is unlikely that most of them will progress into full-blown demyelinating lesions. Preactive lesions are not associated with blood–brain barrier disruption, suggesting that an intrinsic trigger of innate immune activation, rather than extrinsic factors crossing a damaged blood–brain barrier, induces the formation of clusters of activated microglia.</p