Do β-Defensins and Other Antimicrobial Peptides Play a Role in Neuroimmune Function and Neurodegeneration?

It is widely accepted that the brain responds to mechanical trauma and development of most neurodegenerative diseases with an inflammatory sequelae that was once thought exclusive to systemic immunity. Mostly cationic peptides, such as the β-defensins, originally assigned an antimicrobial function are now recognized as mediators of both innate and adaptive immunity. Herein supporting evidence is presented for the hypothesis that neuropathological changes associated with chronic disease conditions of the CNS involve abnormal expression and regulatory function of specific antimicrobial peptides. It is also proposed that these alterations exacerbate proinflammatory conditions within the brain that ultimately potentiate the neurodegenerative process

Molecular Pathogenesis of Alzheimer’s Disease: Reductionist versus Expansionist Approaches

Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by two hallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century ago these hallmark lesions were purified and their protein constituents identified, precipitating an avalanche of molecular studies as well as substantial optimism about successful therapeutic intervention. In 2009, we now have copious knowledge on the biochemical cascades that produce these proteins, the different modifications and forms in which these proteins exist, and the ability to selectively target these proteins for therapeutic intervention on an experimental basis. At the same time, there has been no discernible alteration in the natural course of AD in humans. While it may be that the complexity of AD will exceed our capacity to make significant treatment progress for decades or more, a paradigm shift from the reductionism that defines amyloid-β and tau hypotheses, to one that more accurately reflects the meaning of neuropathological changes, may be warranted. We and others have demonstrated that AD pathology is a manifestation of cellular adaptation, specifically as a defense against oxidative injury. As such, AD pathology is therefore a host response rather than a manifestation of cytotoxic protein injury, and is unlikely to be a fruitful target for therapeutic intervention. An “expansionist” view of the disease, we believe, with oxidative stress as a pleiotropic and upstream process, more aptly describes the relationship between various and numerous molecular alterations and clinical disease

Expression of CD74 is increased in neurofibrillary tangles in Alzheimer's disease

Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized by progressive memory loss. Pathological markers of AD include neurofibrillary tangles, accumulation of amyloid-β plaques, neuronal loss, and inflammation. The exact events that lead to the neuronal dysfunction and loss are not completely understood. However, pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor α, are increased in AD, along with gene expression of major histocompatibility complex (MHC) class II molecules and macrophage migration inhibitory factor (MIF). MHC class II molecules are found in microglia of the brain, while MIF is found in both microglia and neurons of the hypothalamus, hippocampus, and cortex. MIF is not only a lymphocyte mediator but also a pituitary factor with endocrine properties and can mediate phosphorylation of the extracellular signal-regulated kinase-1/2 MAP kinases pathway. In this study, we looked at CD74, an integral membrane protein that acts as both a chaperone for MHC class II molecules as well as a receptor binding site for MIF. CD74 was recently found to be increased in microglia in AD cases compared to age-matched controls, but has not been reported in neurons. In our analysis, immunohistochemistry revealed a significant increase in CD74 primarily in neurofibrillary tangles, amyloid-β plaques, and microglia. This is the first finding to our knowledge that CD74 is increased in neurons of AD cases compared to age-matched control cases

Electromagnetic Interference in an Implantable Loop Recorder Caused by a Portable Digital Media Player

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75458/1/j.1540-8159.2008.01188.x.pd

Synthesis, Molecular Structure, and 1H NMR Analysis of Bis(tetraphenylcyclopentadienyl)ruthenium(II)

Reaction of [Ru(p-cymene)Cl2]2 with K(η5-C5HPh4) in refluxing diglyme yields (η5-C5Ph4)2Ru in ca 50% yield. The complex was not susceptible to oxidation or reduction. (C5HPH4)2Ru crystallizes in the triclinic P1 space group with a = 8.549(4), b = 10.793(4), c = 12.842(5) Å, α = 65.98(3), β = 73.10(3), γ = 83.49(3)° and Z = 1. The least-squares data refined to R(F) = 3.53% and R(wF = 3.82% for the 3952 independent observed reflections with Fo ≥ 5σ(Fo). The metal-centroid distance is 1.832(2) Å and all other bond lengths and angles are similar to other octaphenylmetallocenes. 1H NMR analysis employing 2D J-resolved, COSY and low temperature techniques allowed assignment of all protons in the molecule. The motional processes of the phenyl groups are discussed

Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease

Aberrant neuronal re-entry into the cell cycle is emerging as a potential pathological mechanism in Alzheimer disease (AD). However, while cyclins, cyclin dependent kinases (CDKs), and other mitotic factors are ectopically expressed in neurons, many of these proteins are also involved in other pathological and physiological processes, generating continued debate on whether such markers are truly indicative of a bona fide cell cycle process. To address this issue, here we analyzed one of the minichromosome maintenance (Mcm) proteins that plays a role in DNA replication and becomes phosphorylated by the S-phase promoting CDKs and Cdc7 during DNA synthesis. We found phosphorylated Mcm2 (pMcm2) markedly associated with neurofibrillary tangles, neuropil threads, and dystrophic neurites in AD but not in aged-matched controls. These data not only provide further evidence for cell cycle aberrations in AD, but the cytoplasmic, rather than nuclear, localization of pMcm2 suggests an abnormal cellular distribution of this important replication factor in AD that may explain resultant cell cycle stasis and consequent neuronal degeneration

Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson's disease

Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy body dementia (LBD). Whereas α-synuclein has been found to be the major component of the Lewy body, the mechanisms by which neurons degenerate, as well as basic mechanisms involved in the formation of α-synuclein-related inclusions, remain obscure. We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and α-synuclein may be key

On the alpha formalism for the common envelope interaction

The {\alpha}-formalism is a common way to parametrize the common envelope interaction between a giant star and a more compact companion. The {\alpha} parameter describes the fraction of orbital energy released by the companion that is available to eject the giant star's envelope. By using new, detailed stellar evolutionary calculations we derive a user-friendly prescription for the {\lambda} parameter and an improved approximation for the envelope binding energy, thus revising the {\alpha} equation. We then determine {\alpha} both from simulations and observations in a self consistent manner. By using our own stellar structure models as well as population considerations to reconstruct the primary's parameters at the time of the common envelope interaction, we gain a deeper understanding of the uncertainties. We find that systems with very low values of q (the ratio of the companion's mass to the mass of the primary at the time of the common envelope interaction) have higher values of {\alpha}. A fit to the data suggests that lower mass companions are left at comparable or larger orbital separations to more massive companions. We conjecture that lower mass companions take longer than a stellar dynamical time to spiral in to the giant's core, and that this is key to allowing the giant to use its own thermal energy to help unbind its envelope. As a result, although systems with light companions might not have enough orbital energy to unbind the common envelope, they might stimulate a stellar reaction that results in the common envelope ejection.Comment: 17 pages, 8 figures. Accepted by MNRA