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      Effects of soluble β-amyloid on the release of neurotransmitters from rat brain synaptosomes

      alzheimer’s disease, beta-amyloid, dopamine release, nicotinic receptors, muscarinic receptors

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          Abstract

          Contradictory results have been reported on the interaction of beta-amyloid (Aβ) with cholinergic receptors. The present paper investigates the modulatory effect of Aβ1-40 on the neurotransmitter release evoked by nicotinic (nAChRs) and muscarinic (mAChRs) receptors. Aβ1-40 inhibits both nicotinic and muscarinic-evoked [3H]DA overflow from rat nerve endings. Added to perfusion medium, Aβ1-40 is able to enter into synaptosomes; it exerts its inhibitory effect at extracellular sites when release is stimulated by nAChRs and intracellularly when release is evoked by mAChRs. Moreover, our data show that Aβ1-40 acts as non competitive antagonist of heteromeric α4β2* but not of α3β4* nAChRs which modulate [3H]NA overflow. Positive allosteric modulators of nAChRs counteract its inhibitory effect. It might be that compounds of this type could be useful to prevent, slow down the appearance or reverse the cognitive decline typical of the normal processes of brain aging.

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          Most cited references 52

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          A specific amyloid-beta protein assembly in the brain impairs memory.

          Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
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            Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.

            A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-beta protein interferes with cognitive function. Soluble oligomeric forms of amyloid-beta, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although beta-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-beta moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
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              Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.

              Oxidative stress is a major aspect of Alzheimer disease (AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of Abeta oligomers (also known as ADDLs). ADDLs are known to accumulate in brain tissue of AD patients and are considered centrally related to pathogenesis. Using hippocampal neuronal cultures, we found that ADDLs stimulated excessive formation of reactive oxygen species (ROS) through a mechanism requiring N-methyl-d-aspartate receptor (NMDA-R) activation. ADDL binding to neurons was reduced and ROS formation was completely blocked by an antibody to the extracellular domain of the NR1 subunit of NMDA-Rs. In harmony with a steric inhibition of ADDL binding by NR1 antibodies, ADDLs that were bound to detergent-extracted synaptosomal membranes co-immunoprecipitated with NMDA-R subunits. The NR1 antibody did not affect ROS formation induced by NMDA, showing that NMDA-Rs themselves remained functional. Memantine, an open channel NMDA-R antagonist prescribed as a memory-preserving drug for AD patients, completely protected against ADDL-induced ROS formation, as did other NMDA-R antagonists. Memantine and the anti-NR1 antibody also attenuated a rapid ADDL-induced increase in intraneuronal calcium, which was essential for stimulated ROS formation. These results show that ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux. This response provides a pathologically specific mechanism for the therapeutic action of memantine, indicates a role for ROS dysregulation in ADDL-induced cognitive impairment, and supports the unifying hypothesis that ADDLs play a central role in AD pathogenesis.
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                Author and article information

                Journal
                4098032
                10.3389/fnagi.2014.00166

                http://creativecommons.org/licenses/by/3.0/

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