Soluble beta amyloid evokes alteration in brain norepinephrine levels: role of nitric oxide and interleukin-1

Alzheimer's disease is an age-related neurodegenerative disorder that is characterized by a progressive loss of memory and deterioration of higher cognitive functions. The brain of an individual with Alzheimer's disease exhibits extracellular plaques of aggregated beta-amyloid protein (Abeta), intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Abeta accumulation may trigger or contribute to the process of neurodegeneration. However, the mechanisms whereby Abeta induces basal forebrain cholinergic cell loss and cognitive impairment remain obscure. Physiologically relevant concentrations of Abeta-related peptides have acute, negative effects on multiple aspects of acetylcholine (ACh) synthesis and release, without inducing toxicity. These data suggest a neuromodulatory influence of the peptides on central cholinergic functions. Long-term exposure to micromolar Abeta induces cholinergic cell toxicity, possibly via hyperphosphorylation of tau protein. Conversely, activation of selected cholinergic receptors has been shown to alter the processing of the amyloid precursor protein as well as phosphorylation of tau protein. A direct interaction between Abeta and nicotinic ACh receptors has also been demonstrated. This review addresses the role of Abeta-related peptides in regulating the function and survival of central cholinergic neurons and the relevance of these effects to cholinergic deficits in Alzheimer's disease. Understanding the functional interrelations between Abeta peptides, cholinergic neurons and tau phosphorylation will unravel the biologic events that precede neurodegeneration and may lead to the development of more effective pharmacotherapies for Alzheimer's disease.

It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, and AID's dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro, and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.

Amyloid-beta (Abeta), a peptide thought to play a crucial role in Alzheimer's disease (AD), has many targets that, in turn, activate different second-messenger cascades. Interestingly, Abeta has been found to markedly impair hippocampal long-term potentiation (LTP). To identify a new pathway that might be responsible for such impairment, we analyzed the role of the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK)/cAMP-responsive element-binding protein (CREB) cascade because of its involvement in LTP. The use of the NO donor 2-(N,N-dethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO), the sGC stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine, or the cGMP-analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP reversed the Abeta-induced impairment of CA1-LTP through cGK activation. Furthermore, these compounds reestablished the enhancement of CREB phosphorylation occurring during LTP in slices exposed to Abeta. We also found that Abeta blocks the increase in cGMP immunoreactivity occurring immediately after LTP and that DEA/NO counteracts the effect of Abeta. These results strongly suggest that, when modulating hippocampal synaptic plasticity, Abeta downregulates the NO/cGMP/cGK/CREB pathway; thus, enhancement of the NO/cGMP signaling may provide a novel approach to the treatment of AD and other neurodegenerative diseases with elevated production of Abeta.