cAMP delays beta-amyloid (25-35) induced cell death in rat cortical neurons

Abstract

Beta-amyloid (A beta) accumulation is believed to contribute to neuronal cell death in Alzheimer's disease. To understand the role of cAMP in the regulation of A beta induced cell death, we used 8-chlorophenylthio-cAMP (8-CPT-cAMP, a cAMP analog) to raise intracellular cAMP levels. Exposure of rat cortical neurons to A beta(25-35) resulted in a gradual increase in lactate dehydrogenase (LDH) over 48 h, which was preceded by a transient elevation in caspase-3-like activity. In the presence of 8CPT-cAMP, both caspase-3 activity and LDH release was significantly reduced. These data suggest that elevation of intracellular cAMP levels attenuate A beta-induced neurotoxicity and may delay or prevent the onset of A beta-induced neurodegeneration.

Adenosine A2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

“…2005), we investigated whether the neuroprotective effects afforded by SCH58261 involved this pathway. As observed in the Figure 7A, the manipulation of the cAMP/PKA pathway influences A␤ 1-42 -induced neurotoxicity, as described by others (Parvathenani et al, 2000;Gong et al, 2004;Shrestha et al, 2006). In fact, the activation of PKA with the cell-permeable cAMP analog 8-Br-cAMP (200 M) attenuated A␤ 1-42 -induced neurotoxicity, an effect prevented by the PKA inhibitor H-89 (1 M) (Fig.…”

“…For historical reasons, there is a general consensus that A 2A Rs signal through activation of the adenylate cyclase/cAMP/PKA pathway (Fredholm et al, 2005). However, this is unlikely to be the relevant transducing system related to A 2A R control of neurodegeneration since enhanced cAMP levels afford neuroprotection against A␤-induced neurotoxicity (Parvathenani et al, 2000;Gong et al, 2004;Shrestha et al, 2006), whereas it is A 2A R blockade (expected to decrease cAMP levels) that affords neuroprotection. Accordingly, neuroprotection afforded by A 2A R blockade against A␤-induced neurotoxicity was insensitive to the PKA inhibitor H-89, which prevented neuroprotection afforded by enhanced cAMP levels.…”

Cyclic AMP Inhibition of Tumor Necrosis Factor α Production Induced by Amyloidogenic C-Terminal Peptide of Alzheimer's Amyloid Precursor Protein in Macrophages: Involvement of Multiple Intracellular Pathways and Cyclic AMP Response Element Binding Protein

“…In this regard, cell-permeable cAMP analogs that can reduce CT105-induced inflammatory response without affecting cell viability may represent a promising aspect of a combined strategy for current, largely symptomatic treatments, aimed at enhancing the levels of depleted neurotrans-mitters, particularly acetylcholine. Recent studies reporting the attenuation of A␤-induced neurotoxicity by the elevation of intracellular cAMP levels (Parvathenani et al, 2000) and the potentiation of A␤-induced cortical inflammation by noradrenergic depletion (Heneka et al, 2002) further support our findings.…”

P2X7 Mediates Superoxide Production in Primary Microglia and Is Up-regulated in a Transgenic Mouse Model of Alzheimer's Disease

“…Isolation of Cortical Neurons-Primary cortical cell cultures were prepared from embryos of timed pregnant Sprague-Dawley rats at E14 (18). Briefly, the cortex triturated in DNase/Protease dissociation buffer was centrifuged and resuspended in PC-1 SF medium (BioWhittaker).…”

“…Immunoblotting-Immunoblotting was performed as described previously (18). Briefly 25 g of protein was fractionated on a 10% SDS-PAGE gel, transferred to polyvinylidene difluoride membrane, and blocked in 5% milk/Tris-buffered saline containing 0.1% Tween 20 for 2 h. The membrane were washed and incubated overnight with antibodies specific for phospho-p42/44 MAPK (Thr-202/Tyr-204), phosphop38 MAPK (Thr-180/Tyr-182) diluted 1:1000 in TBST containing 5% bovine serum albumin.…”