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This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer's disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1-42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.

Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.

Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting saltatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e., mechanical allodynia). Our earlier (Liu et al., 2012) and present data demonstrate that a single injection of a myelin basic protein-derived peptide (MBP84-104) into an intact sciatic nerve produces a robust and long-lasting (>30days) mechanical allodynia in female rats. The MBP84-104 peptide represents the immunodominant epitope and requires T cells to maintain allodynia. Surprisingly, only systemic gabapentin (a ligand of voltage-gated calcium channel α2δ1), but not ketorolac (COX inhibitor), lidocaine (sodium channel blocker) or MK801 (NMDA antagonist) reverse allodynia induced by the intrasciatic MBP84-104. The genome-wide transcriptional profiling of the sciatic nerve followed by the bioinformatics analyses of the expression changes identified interleukin (IL)-6 as the major cytokine induced by MBP84-104 in both the control and athymic T cell-deficient nude rats. The intrasciatic MBP84-104 injection resulted in both unilateral allodynia and unilateral IL-6 increase the segmental spinal cord (neurons and astrocytes). An intrathecal delivery of a function-blocking IL-6 antibody reduced the allodynia in part by the transcriptional effects in large-diameter primary afferents in DRG. Our data suggest that MBP regulates IL-6 expression in the nervous system and that the spinal IL-6 activity mediates nociceptive processing stimulated by the MBP epitopes released after damage or disease of the somatosensory nervous system.

Protected plant and wildlife species that grow, forage, nest, roost, or migrate near the Washington State Department of Transportation (WSDOT) highway system may be susceptible to impacts from routine maintenance activities. In response to community-driven concerns related to the conservation of protected terrestrial species and due to the lack of existing guidance for maintenance personnel when protected-species conflicts arose, WSDOT biologists and maintenance personnel worked together to develop new guidance. The purpose of the guidance is to provide maintenance personnel with resources that identify which projects occur in sensitive plant and wildlife areas and identify best management practices (BMPs) that can be implemented to minimize or avoid impacts to protected terrestrial species in Washington State. Existing sensitive-species data and aerial photographs were used to identify locations of sensitive species and habitats and to develop guidance. To verify habitat presence, biologists conducted site visits to areas identified as possible sensitive habitats. The guidance document is in the form of a field handbook presented in a step-by-step format to facilitate use by WSDOT maintenance personnel. The guidance document provides maps and descriptions of sensitive areas, each identified by state route and milepost. Species information, such as species name, nest sites, wintering sites, or locations of sensitive habitats, are not identified in the guidance document. Alternatively, biologists placed the species into groups based on habitat needs and identified only the state-route mileposts that fall within each sensitive area. This process helped WSDOT prevent publicizing sensitive wildlife data in the guidance documents and avoided the need for evaluation of habitat by maintenance personnel. Common maintenance functions were also broken down into groups. For each sensitive location and maintenance function group, a list of BMPs is provided. BMPs may include timing restrictions, equipment use restrictions, or overall activities that should be avoided during certain seasons. The document does not address all possible conditions that may arise during maintenance operations that could affect protected terrestrial species. Maintenance staff consult with their Regional Maintenance Environmental Coordinator prior to initiating any activity that is not addressed by the guidance document or if there is any uncertainty about the applicability of the guidance. Maintenance activities that are not able to comply with the guidance typically require a field review by a biologist and the development of site-specific BMPs. Maintenance personnel do not follow this guidance for emergency actions because separate procedures were previously developed that adequately address protected species compliance for emergency maintenance actions. This project is currently being piloted with the Olympic Region Maintenance Program. Training courses conducted at individual maintenance sheds have provided opportunity for discussion and question and answer sessions. Biologists and maintenance personnel have had the opportunity to work together to learn each other’s programs, perspectives, and observations to improve the effectiveness of the environmental compliance guidance. The WSDOT Highway Maintenance Environmental Compliance Guidance for Protected Terrestrial Species Program has helped the Maintenance Program conduct