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Research has been conducted on the guanylyl cyclase receptors which are important during the phototransduction in the vertebrate photoreceptor cells. The activation mechanism of the guanylyl cyclase-activating proteins and their specificity have been investigated via generation of the soluble and active truncated guanylyl cyclase receptors and fusion proteins between guanylyl cyclase receptors' intracellular domains and full-length guanylyl cyclase-activating proteins.

The intracellular fragment of guanylyl cyclase 1 (GC1), residues 491-1110, were synthesized as a set of 15 amino acids long that partially overlap peptides on the surface of individual pins arranged in a microtiter plate format. This was done to identify regions within photoreceptor GC1 interacting with GC-activating proteins (GCAPs). The results suggested that GC1-GCAP interaction leads to adenylyl cyclase (AC) activation and that the modulation of both GC and AC activity may be done via their own regions in catalytic domains despite interaction with varied activating proteins.

Research was conducted to test whether guanylate cyclase-activating protein 1 (GCAP1) remains in a complex with guanylate cyclase 1 regardless of its Ca2+ occupancy. Sense primers were utilized to generate point mutations while GCAP1 concentrations were determined with a spectrophotomer. Results indicated that GCAP2 dissociated from membranes when it was saturated with CA2+ and also showed that GCAP1 established a stable complex with guanylate cyclase 1.

Abstract Background Innate immune activation, including a role for cluster of differentiation 14/toll-like receptor 4 co-receptors (CD14/TLR-4) co-receptors, has been implicated in paracrine damage to neurons in several neurodegenerative diseases that also display stratification of risk or clinical outcome with the common alleles of the apolipoprotein E gene (APOE): APOE2, APOE3, and APOE4. Previously, we have shown that specific stimulation of CD14/TLR-4 with lipopolysaccharide (LPS) leads to greatest innate immune response by primary microglial cultures from targeted replacement (TR) APOE4 mice and greatest p38MAPK-dependent paracrine damage to neurons in mixed primary cultures and hippocampal slice cultures derived from TR APOE4 mice. In contrast, TR APOE2 astrocytes had the highest NF-kappaB activity and no neurotoxicity. Here we tested the hypothesis that direct activation of CD14/TLR-4 in vivo would yield different amounts of paracrine damage to hippocampal sector CA1 pyramidal neurons in TR APOE mice. Methods We measured in vivo changes in dendrite length in hippocampal CA1 neurons using Golgi staining and determined hippocampal apoE levels by Western blot. Neurite outgrowth of cultured primary neurons in response to astrocyte conditioned medium was assessed by measuring neuron length and branch number. Results Our results showed that TR APOE4 mice had slightly but significantly shorter dendrites at 6 weeks of age. Following exposure to intracerebroventricular LPS, there was comparable loss of dendrite length at 24 hr among the three TR APOE mice. Recovery of dendrite length over the next 48 hr was greater in TR APOE2 than TR APOE3 mice, while TR APOE4 mice had failure of dendrite regeneration. Cell culture experiments indicated that the enhanced neurotrophic effect of TR APOE2 was LDL related protein-dependent. Conclusion The data indicate that the environment within TR APOE2 mouse hippocampus was most supportive of dendrite regeneration while that within TR APOE4 hippocampus failed to support dendrite regeneration in this model of reversible paracrine damage to neurons from innate immune activation, and suggest an explanation for the stratification of clinical outcome with APOE seen in several degenerative diseases or brain that are associated with activated innate immune response.

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Background: Brain-derived neurotrophic factor (BDNF) is an activity-dependent secreted protein that is critical to organization of neuronal networks and synaptic plasticity, especially in the hippocampus. We tested hypothesis that reduced CSF BDNF is associated with age-related cognitive decline. Methodology/Principal Findings, and Conclusions/Significance: CSF concentration of BDNF, Aβ42 and total tau were measured in 128 cognitively normal adults (Normals), 21 patients with Alzheimer's disease (AD), and nine patients with Mild Cognitive Impairment. Apolipoprotein E and BDNF SNP rs6265 genotype were determined. Neuropsychological tests were performed at baseline for all subjects and at follow-up visits in 50 Normals. CSF BDNF level was lower in AD patients compared to age-matched Normals (p = 0.02). CSF BDNF concentration decreased with age among Normals and was higher in women than men (both p<0.001). After adjusting for age, gender, education, CSF Aβ42 and total tau, and APOE and BDNF genotypes, lower CSF BDNF concentration was associated poorer immediate and delayed recall at baseline (both p<0.05) and in follow up of approximately 3 years duration (both p,0.01). Conclusions/Significance: Reduced CSF BDNF was associated with age-related cognitive decline, suggesting a potential mechanism that may contribute in part to cognitive decline in older individuals. [ABSTRACT FROM AUTHOR]