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Microglia play a vital role in maintaining brain homeostasis. Their continuous sensing of surrounding micro‐environments is crucial for their activity. Cross talk between specific neurons and microglia might occur through specific neurotransmitter receptors on microglia. Impairment with this interaction might result in pathological activity of microglia against potential insults. The reason for this activity in many neurodegenerative diseases such as Alzheimer's disease (AD) is not known. However, several papers report of the effects of different neurotransmitter agonists on microglial cells function that relate to their activity in AD. This review aims to summarize those works and to raise potential fundamental questions for future research. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1 alpha (HIF-1α) and purine nucleosides adenosine and inosine are critical mediators of physiological responses to acute and chronic hypoxia. The specific aim of this paper was to evaluate the potential role of HIF-1α in purine-mediated neuroprotection. We show that adenosine and inosine efficiently rescued clonal rat pheochromocytoma (PC12) cells (up to 43.6%) as well as primary cerebellar granule neurons (up to 25.1%) from hypoxic insult, and furthermore, that HIF-1α is critical for purine-mediated neuroprotection. Next, we studied hypoxia or purine nucleoside increased nuclear accumulation of HIF-1α in PC12 cells. As a possible result of increased protein stabilization or synthesis an up to 2.5-fold induction of HIF-1α accumulation was detected. In cerebellar granule neurons, purine nucleosides induced an up to 3.1-fold HIF-1α accumulation in cell lysates. Concomitant with these results, small interfering RNA-mediated reduction of HIF-1α completely abolished adenosine- and inosine-mediated protection in PC12 cells and severely hampered purine nucleoside-mediated protection in primary neurons (up to 94.2%). Data presented in this paper thus clearly demonstrate that HIF-1α is a key regulator of purine nucleoside-mediated rescue of hypoxic neuronal cells. [ABSTRACT FROM AUTHOR]

Phospholipases A2 (PLA2s) are essential enzymes in cells. They are not only responsible for maintaining the structural organization of cell membranes, but also play a pivotal role in the regulation of cell functions. Activation of PLA2s results in the release of fatty acids and lysophospholipids, products that are lipid mediators and compounds capable of altering membrane microdomains and physical properties. Although not fully understood, recent studies have linked aberrant PLA2 activity to oxidative signaling pathways involving NADPH oxidase that underlie the pathophysiology of a number of neurodegenerative diseases. In this paper, we review studies describing the involvement of cytosolic PLA2 in oxidative signaling pathways leading to neuronal impairment and activation of glial cell inflammatory responses. In addition, this review also includes information on the role of cytosolic PLA2 and exogenous secretory PLA2 on membrane physical properties, dynamics, and membrane proteins. Unraveling the mechanisms that regulate specific types of PLA2s and their effects on membrane dynamics are important prerequisites towards understanding their roles in the pathophysiology of Alzheimer’s disease, and in the development of novel therapeutics to retard progression of the disease. [ABSTRACT FROM AUTHOR]

NMDA receptors interact with a variety of intracellular proteins at excitatory synapses. In this paper we show that myosin regulatory light chain (RLC) isolated from mouse brain is a NMDA receptor-interacting protein. Myosin RLC bound directly to the C-termini of both NMDA receptor 1 (NR1) and NMDA receptor 2 (NR2) subunits, rendering the interaction of myosin RLC with NMDA receptors distinct from that of calmodulin which is considered a NR1-interacting protein. Myosin RLC co-localized with NR1 in the dendritic spines of isolated hippocampal neurons, and was co-immunoprecipitated from brain extracts in a complex with NR1, NR2A, NR2B, PSD-95, Adaptor protein-2and myosin II heavy chain. The C0 region of NR1 was necessary and sufficient for binding myosin RLC. Ca2+/calmodulin, but not calmodulin alone, displaced recombinant myosin RLC from the carboxy tail of NR1 indicating that myosin RLC and Ca2+/calmodulin can compete for a common binding site on NR1in vitro. Myosin RLC is the only known substrate for myosin regulatory light chain kinase, which has recently been shown to modulate NMDA receptor function in isolated hippocampal neurons. Our results suggest that an additional level of NMDA receptor regulation may be mediated via a direct interaction with a light chain of myosin II. Thus, myosin RLC–NMDA receptor interactions may contribute to the contractile and motile forces that are placed upon NMDA receptor subunits during changes associated with synaptic plasticity and neural morphogenesis. [ABSTRACT FROM AUTHOR]

Apoptosis is an active process that is regulated by different signalling pathways. One of the more important organelles involved in apoptosis regulation is the mitochondrion. Electron chain transport disruption increases free radical production leading to multiple conductance channel opening, release of cytochrome c and caspase activation. This death pathway can be blocked by anti-apoptotic members of the Bcl-2 protein family that might shift redox potential to a more reduced state, preventing free radical-mediated damage. 6-Hydroxydopamine (6-OHDA) has been widely used to generate Parkinson's disease-like models. It is able to generate free radicals and to induce catecholaminergic cell death. In this paper we have used the human neuroblastoma cell line SH-SY5Y overexpressing Bcl-xL as a model to gain insights into the mechanisms through which Bcl-xL blocks 6-OHDA-induced cell death and to identify the molecular targets for this action. Herein, we present evidence supporting that the Bcl-xL –anti-apoptotic signal pathway seems to prevent mitochondrial multiple conductance channel opening, cytochrome c release and caspase-3 like activity following 6-OHDA treatment in the human neuroblastoma cell line SH-SY5Y. [ABSTRACT FROM AUTHOR]

Many models of Parkinson's disease (PD) have succeeded in replicating dopaminergic neuron loss or α-synuclein aggregation but not the formation of classical Lewy bodies, the pathological hallmark of PD. Our cybrid model of sporadic PD was created by introducing the mitochondrial genes from PD patients into neuroblastoma cells that lack mitochondrial DNA. Previous studies using cybrids have shown that information encoded by mitochondrial DNA in patients contributes to many pathogenic features of sporadic PD. In this paper, we report the generation of fibrillar and vesicular inclusions in a long-term cybrid cell culture model that replicates the essential antigenic and structural features of Lewy bodies in PD brain without the need for exogenous protein expression or inhibition of mitochondrial or proteasomal function. The inclusions generated by PD cybrid cells stained with eosin, thioflavin S, and antibodies to α-synuclein, ubiquitin, parkin, synphilin-1, neurofilament, β-tubulin, the proteasome, nitrotyrosine, and cytochrome c . Future studies of these cybrids will enable us to better understand how Lewy bodies form and what role they play in the pathogenesis of PD. [ABSTRACT FROM AUTHOR]