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Insulin-like growth factor 1 (IGF-1) stimulates α-secretase processing of amyloid precursor protein (APP) and decreases Aβ production. Little is known about the relationship between IGF-1 and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), the protease essential for the production of β-amyloid peptides (Aβ). Here, we investigated the effect of IGF-1 on BACE-1 in PC12 cells. Quantitative polymerase chain reaction analysis and western blot showed that treatment of cells with IGF-1 significantly decreased the levels of BACE-1 mRNA and protein. Furthermore, IGF-1 increased the phosphorylation of Akt and ERK1/2. The presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 and the mitogen-activated protein kinase kinases (MEK) inhibitor PD98059 blocked the effect of IGF-1 on BACE-1. Our data indicated that IGF-1-induced reduction of BACE-1 might involve the PI3-K/Akt and MAPK/ERK1/2 signaling pathways. [ABSTRACT FROM AUTHOR]

In this paper a hypothesis that some special signals (“key-signals” excito-amino acids, β-amyloid peptides and α-synuclein) are not only involved in information handling by the neuronal circuits, but also trigger out substantial structural and/or functional changes in the Central Nervous System (CNS) is introduced. This forces the neuronal circuits to move from one stable state towards a new state, but in doing so these signals became potentially dangerous. Several mechanisms are put in action to protect neurons and glial cells from these potentially harmful signals. However, in agreement with the Red Queen Theory of Ageing (Agnati et al. in Acta Physiol Scand 145:301–309, ), it is proposed that during ageing these neuroprotective processes become less effective while, in the meantime, a shortage of brain plasticity occurs together with an increased need of plasticity for repairing the wear and tear of the CNS. The paper presents findings supporting the concept that such key-signals in instances such as ageing may favour neurodegenerative processes in an attempt of maximizing neuronal plasticity. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of brain dementia characterized by the accumulation of β-amyloid peptides (Aβ) and loss of forebrain cholinergic neurons. Aβ accumulation and aggregation are thought to contribute to cholinergic neuronal degeneration, in turn causing learning and memory deficits, but the specific targets that mediate Aβ neurotoxicity remain elusive. Recently, accumulating lines of evidence have demonstrated that Aβ directly modulates the function of neuronal nicotinic acetylcholine receptors (nAChRs), which leads to the new hypothesis that neuronal nAChRs may serve as important targets that mediate Aβ neurotoxicity. In this review, we summarize current studies performed in our laboratory and in others to address the question of how Aβ modulates neuronal nAChRs, especially nAChR subunit function. [ABSTRACT FROM AUTHOR]

Fibril formation by the Alzheimer's β-amyloid (Aβ) peptide in brain tissue is integral to the Alzheimer's disease pathology. Understanding the conformational properties and the mechanisms triggering aggregation of the Aβ peptides, at an atomic level of detail, is of crucial importance for the design of effective therapeutic agents against this disease. In this work, the conformational transitions and dynamic properties of an amyloidogenic peptide fragment (Aβ10-35) were studied by molecular dynamics simulations in systems modeling infinite dilution and the presence of macromolecular crowding agents (CA). The model system consists of the peptide described with an atomistic force field, the CA represented by inert, quasi-hard spheres and a continuum solvent model. This combined model allowed the simulations to be extended to 100 ns each. Simulations were carried out starting from a completely extended structure, a β-strand structure, and four nuclear magnetic resonance structures in dilute aqueous solution. For all structures, two additional simulations were performed that included the inert CA in the solution and occupied approx 30 and 40% of the volume, respectively. For two of the nuclear magnetic resonance structures, additional simulations were carried out with 35% volume fraction of CA to further examine the diffusive behavior of the peptide. The peptide adopted a collapsed coil conformation in all simulations. The results of the simulations in dilute solution showed reasonable qualitative agreement with experimental and other simulation results, whereas the presence of volume excluding agents resulted in some distinct changes in properties (e.g., an increase in the appearance of transient β-structure or decreases in diffusivity with increasing CA concentration). At the same time, internal motion such as order parameter or atomic root mean square fluctuations showed less systematic responses to volume exclusion. [ABSTRACT FROM AUTHOR]