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To date great number of articles were devoted to cholesterol (chol) but …
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AMYLOID b IS A POTENTIAL PHYSIOLOGICAL ANTIOXIDANT FOR LIPOPROTEINS IN CEREBROSPINAL FLUID AND PLASMA
Increased oxidative stress is related to the Alzheimer's development, and amyloid beta protein (Ab) is considered to be an important prooxidant in this process [8]. To induce oxidation, however, Ab must be present at high concentrations, typically in a micromolar range [9]. In addition, an Ab preparation must be 'aged' to yield Ab aggregates and fibrils [10]. In vitro, Ab is readily aggregated by transition metal ions [11]; in contrast, in the absence of metals Ab is monomeric. The presence of transition metals is not only required for Ab aggregation but also for its prooxidative activity [12]. Therefore, Ab toxicity is mediated by a direct interaction between Ab and transition metals with subsequent generation of reactive oxygen species (ROS).
The requirement of fibrillation and transition metals for the prooxidative activity of Ab can be understood taking into account its redox properties. In order to function as a prooxidant, Ab must first bind metals to its metal-binding site(s) at His residues [13] and then reduce them in its metal-reducing site at Met35 residue [14] in order to produce ROS.
However, metals bind to the N-terminal hydrophilic part of Ab, whereas metal reduction occurs at its C-terminal part. Since metals must be placed in the vicinity of the reductant to be reduced, fibrillation is likely to fulfil this task by forming complexes where metal atoms bound to the N-terminal part of one molecule of Ab, at the same time might be available for the reductive Met35 residues belonging to other Ab molecules. The resulting reduced transition metal ions can participate in further redox reactions, generating various free radical species. Due to relatively slow reduction of metals by Ab, the above mechanism can only be operative at high (micromolar) concentrations of the Ab peptide.
In contrast to prooxidative properties, an antioxidative activity of Ab peptides (that contradicts the dogmatic view on Ab as toxic) has been barely studied. We have shown that at low-nanomolar concentrations (i.e., those of soluble Ab in CSF and plasma), exogenously added Ab inhibits metal-catalyzed oxidation of lipoproteins of human CSF and plasma [15, 16]. The effect is observed at the peptide concentration reported for biological fluids (0.1-1.0 nM); at higher concentration of Ab its antioxidant action is abolished. In contrast, all Ab peptides are unable to considerably influence metal-independent lipoprotein oxidation, suggesting that the antioxidative activity of Ab is mainly mediated by chelating transition metal ions. Endogenous Ab present in CSF can also act as an antioxidant, as is suggested by the positive correlation between CSF resistance to oxidation and the CSF level of Ab [17].
Our data were confirmed by Zou et al. [18] who reported potent antioxidant activity of Ab in neuronal cells in the presence of transition metals. Ab protected neurons against toxic action of copper and iron; the effect strictly depended on the aggregation state of the peptide. Monomeric Ab was protective even at micromolar concentrations, whereas aggregated Ab lost its antioxidant properties. These results are consistent with earlier observations of Whitson et al., Yankner et al. and Koo et al. who showed that at low-nanomolar concentrations Ab is monomeric, non-toxic and exerts beneficial effect on neuron survival, axonal length and neurite outgrowth [19, 20, 21]. We propose that all these activities may be related to antioxidative properties of the peptide.
Mechanistically, antioxidative activity of Ab can be related to the fact that in lipoproteins, a metal-binding region of Ab expresses greater hydrophilic properties and extends into the outer aqueous phase where it can bind transition metals and inhibit metal-catalysed oxidation. In this regard it is important to note that neuronal cell cultures secrete a high molecular weight product, presumably a lipoprotein complex, that possesses an antioxidative activity [22].
As soon as Ab has antioxidative properties on one hand, and is secreted by cells as a part of lipoprotein complexes [1, 3, 23] on another, it is well possible that Ab is secreted by cells to serve as a natural antioxidant for lipoproteins. Ab can bind transition metal ions in inactive form and prevents them from catalyzing oxidation of lipoproteins and other biomolecular complexes. Amphiphilic properties of Ab may allow extracellular chelation of metal ions that escape binding by hydrophilic chelators.
AMYLOID b RESTORES HIPPOCAMPAL LONG TERM POTENTIATION: A CENTRAL ROLE FOR CHOLESTEROL
In our most recent study [24] we attempted to dissect out the role for Ab in the synaptic plasticity in brain slices from adult male rat hippocampus under the condition [2] that we characterised previously with regard to cholesterol and phospholipid synthesis. The prolonged maintanance of slices in a test tube for more then twenty hours in our experimental setup preserved synaptic function (input/output curve, a basic measure of synaptic function, for example) but abrogated synaptic plasticity (LTP). Ab protein of the 1-40 aminoacids’ molecule length (representing the major form of soluble Ab) rescued LTP while cholesterol synthesis inhibition with a statin abolished the LTP restoration by the peptide.
Our observation implies an intriguing perspective that Ab protein is a functional player in an activity-dependent cholesterol neurochemical pathways and in synaptic structure-functional plasticity [2, 3, 4, 24, 25]. The finding also supports our proposed hypothesis that the change in Ab biochemistry in Alzheimer's disease and related disorders is a functional (but NOT pathologic [25, 26, fr10]) compensatory phenomenon aiming to counterbalance impaired cholesterol dynamics and associated neurotransmission and synaptic plasticity [3, 4, 5, 25]. Such cholesterol mediated failure of synaptic function and neural degeneration [2, 4] in our view may represent the cause of the major sporadic form of Alzheimer's disease.
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