Ulrich Eisel

Statins: Mechanisms of neuroprotection

Clinical trials report that the class of drugs known as statins may be neuroprotective in Alzheimers and Parkinsons disease, and further trials are currently underway to test whether these drugs are also beneficial in multiple sclerosis and acute stroke treatment. Since statins are well tolerated and have relatively few side effects, they may be considered as viable drugs to ameliorate neurodegenerative diseases. However, the mechanism of their neuroprotective effects is only partly understood. In this article, we review the current data on the neuroprotective effects of statins and their underlying mechanisms. In the first section, we detail the mechanisms by which statins affect cellular signalling. The primary action of statins is to inhibit cellular cholesterol synthesis. However, the cholesterol synthesis pathway also has several by-products, the non-sterol isoprenoids that are also important in cellular functioning. Furthermore, reduced cholesterol levels may deplete the cholesterol-rich membrane domains known as lipid rafts, which in turn could affect cellular signalling. In the second section, we summarize how the effects on signalling translate into general neuroprotective effects through peripheral systems. Statins improve blood-flow, reduce coagulation, modulate the immune system and reduce oxidative damage. The final section deals with the effects of statins on the central nervous system, particularly during Alzheimers and Parkinsons disease, stroke and multiple sclerosis.

Tumor necrosis factor receptor cross‐talk

Extensive research has been performed to unravel the mechanistic signaling pathways mediated by tumor necrosis factor receptor 1 (TNFR1), by contrast there is limited knowledge on cellular signaling upon activation of TNFR2. Recently published data have revealed that these two receptors not only function independently, but also can influence each other via cross‐talk between the different signaling pathways initiated by TNFR1 and TNFR2 stimulation. Furthermore, the complexity of this cross‐talk is also dependent on the different signaling kinetics between TNFR1 and TNFR2, by which a delicate balance between cell survival and apoptosis can be maintained. Some known signaling factors and the kinetics that are involved in the receptor cross‐talk between TNFR1 and TNFR2 are the topic of this review.

Inflammation and NF-κB in Alzheimer's Disease and Diabetes

Inflammatory processes are a hallmark of many chronic diseases including Alzheimers disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimers disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappaB might be involved in both diabetes mellitus and Alzheimers disease and whether these factors can link both diseases.

Inflammation and NF-kappa B in Alzheimer's Disease and Diabetes

Inflammatory processes are a hallmark of many chronic diseases including Alzheimers disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimers disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappaB might be involved in both diabetes mellitus and Alzheimers disease and whether these factors can link both diseases.

Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease

Alzheimers disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF‐α. TNF‐α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF‐α‐induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β‐amyloid toxicity. Moreover, Lcn2 silences a TNFR2‐mediated protective neuronal signaling cascade in neurons, pivotal for TNF‐a‐mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.—Naudé, P.J. W., Nyakas, C., Eiden, L. E., Ait‐Ali, D., van der Heide, R., Engelborghs, S., Luiten, P. G. M., De Deyn, P. P., den Boer, J. A., Eisel, U. L. M. Lipocalin 2: Novel component of proinflammatory signaling in Alzheimers disease. FASEB J. 26, 2811–2823 (2012). www.fasebj.org

Interleukin-6 upregulates neuronal adenosine A1 receptors: implications for neuromodulation and neuroprotection.

The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A1 receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A1 receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.

TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappa B-dependent up-regulation of K(Ca)2.2 channels

Previous studies have shown that tumor necrosis factor‐alpha (TNF‐α) induces neuroprotection against excitotoxic damage in primary cortical neurons via sustained nuclear factor‐kappa B (NF‐κB) activation. The transcription factor NF‐κB can regulate the expression of small conductance calcium‐activated potassium (KCa) channels. These channels reduce neuronal excitability and as such may yield neuroprotection against neuronal overstimulation. In the present study we investigated whether TNF‐α‐mediated neuroprotective signaling is inducing changes in the expression of small conductance KCa channels. Interestingly, the expression of KCa2.2 channel was up‐regulated by TNF‐α treatment in a time‐dependent manner whereas the expression of KCa2.1 and KCa2.3 channels was not altered. The increase in KCa2.2 channel expression after TNF‐α treatment was shown to be dependent on TNF‐R2 and NF‐κB activation. Furthermore, activation of small conductance KCa channels by 6,7‐dichloro‐1H‐indole‐2,3‐dione 3‐oxime or cyclohexyl‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐pyrimidin‐4‐yl]‐amine‐induced neuroprotection against a glutamate challenge. Treatment with the small conductance KCa channel blocker apamin or KCa2.2 channel siRNA reverted the neuroprotective effect elicited by TNF‐α. We conclude that treatment of primary cortical neurons with TNF‐α leads to increased KCa2.2 channel expression which renders neurons more resistant to excitotoxic cell death.

Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation

In diverse neuronal processes ranging from neuronal survival to synaptic plasticity cyclic adenosine monophosphate (cAMP)-dependent signaling is tightly connected with the protein kinase B (PKB)/Akt pathway but the precise nature of this connection remains unknown. In the current study we investigated the effect of two mainstream pathways initiated by cAMP, cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epac1 and Epac2) on PKB/Akt phosphorylation in primary cortical neurons and HT-4 cells. We demonstrate that PKA activation leads to a reduction of PKB/Akt phosphorylation, whereas activation of Epac has the opposite effect. This effect of Epac on PKB/Akt phosphorylation was mediated by Rap activation. The increase in PKB/Akt phosphorylation after Epac activation could be blocked by pretreatment with Epac2 siRNA and to a somewhat smaller extent by Epac1 siRNA. PKA, PKB/Akt and Epac were all shown to establish complexes with neuronal A-kinase anchoring protein150 (AKAP150). Interestingly, activation of Epac increased phosphorylation of PKB/Akt complexed to AKAP150. From experiments using PKA-binding deficient AKAP150 and peptides disrupting PKA anchoring to AKAPs, we conclude that AKAP150 acts as a key regulator in the two cAMP pathways to control PKB/Akt phosphorylation.

In Silico Study of Full-Length Amyloid β 1−42 Tri- and Penta-Oligomers in Solution

Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimers disease. Using MD simulation techniques, we explored the contributions of the different structural elements of trimeric and pentameric full-length Abeta1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two beta-sheet regions of the aggregates: beta1 (residues 18-26) and beta2 (residues 31-42). MD simulations reveal that the beta-strand twist is a characteristic element of Abeta-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The beta2 portion formed a tightly organized beta-helix, whereas the beta1 portion did not show such a firm structural organization, although it maintained its beta-sheet conformation. Our simulations indicate that the hydrophobic core comprising the beta2 portion of the aggregate is a crucial stabilizing element in the Abeta aggregation process. On the basis of these structure-stability findings, the beta2 portion emerges as an optimal target for further antiamyloid drug design.

Neuroprotective and neurodegenerative effects of the chronic expression of tumor necrosis factor alpha in the nigrostriatal dopaminergic circuit of adult mice

Tumor necrosis factor (TNF)-α, a pro-inflammatory cytokine, has been implicated in both neuronal death and survival in Parkinsons disease (PD). The substantia nigra (SN), a CNS region affected in PD, is particularly susceptible to inflammatory insults and possesses the highest density of microglial cells, but the effects of inflammation and in particular TNF-α on neuronal survival in this region remains controversial. Using adenoviral vectors, the CRE/loxP system and hypomorphic mice, we achieved chronic expression of two levels of TNF-α in the SN of adult mice. Chronic low expression of TNF-α levels reduced the nigrostriatal neurodegeneration mediated by intrastriatal 6-hydroxydopamine administration. Protective effects of low TNF-α level could be mediated by TNF-R1, GDNF, and IGF-1 in the SN and SOD activity in the striatum (ST). On the contrary, chronic expression of high levels of TNF-α induced progressive neuronal loss (63% at 20 days and 75% at 100 days). This effect was accompanied by gliosis and an inflammatory infiltrate composed almost exclusively by monocytes/macrophages. The finding that chronic high TNF-α had a slow and progressive neurodegenerative effect in the SN provides an animal model of PD mediated by the chronic expression of a single cytokine. In addition, it supports the view that cytokines are not detrimental or beneficial by themselves, i.e., their level and time of expression among other factors can determine its final effect on CNS damage or protection. These data support the view that new anti-parkinsonian treatments based on anti-inflammatory therapies should consider these dual effects of cytokines on their design.