Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity: Relevance to Alzheimer's disease

1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer' s disease (AD) brain in areas subserving information acquisition arid proce ssing, and memory formation. A beta fragments are producedin a process of a bnormal proteolytic cleavage of their precursor, the amyloid precursor prot ein (APP). While conflicting data exist in the literature on the roles of A beta s in the brain, and particularly in AD, recent studies have provided firm experimental evidence for the direct neurotoxic properties of A beta. 2. Sequence analysis of A beta s revealed a high degree of evolutionary con servation and inter-species homology of the A beta amino acid sequence. In contrast, synthetic A beta fragments, even if modified fluorescent or isoto pe-labeled derivatives, are pharmacological candidates for in vitro and in vivo modeling of their cellular actions; During the past decade, acute inje ction, prolonged mini-osmotic brain perfusion approaches or A beta infusion s into the blood circulation were developed in order to investigate the eff ects of synthetic A beta s, whereas transgenic models provided insight into the distinct molecular steps of pathological APP cleavage. 3. The hippocampus, caudate putamen, amygdala and neocortex all formed prim ary targets of acute neurotoxicity screening, but functional consequences o f A beta infusions were primarily demonstrated following either intracerebr oventricular or basal forebrain (medial septum or magnocellular basal nucle us (MBN)) infusions of A beta fragments. 4. In vivo investigations confirmed that, while the active core of A beta i s located within the beta(25-35) sequence, the flanking peptide regions inf luence not only the folding properties of the A beta fragments, but also th eir in vivo neurotoxic potentials. 5. It has recently been established that A beta administration deranges neu ron-glia signaling, affects the glial glutamate uptake and thereby induces noxious glutamatergic stimulation of nerve cells. In fact, a critical role for N-methyl-D-aspartate (NMDA) receptors was postulated in the neurotoxic processes. Additionally, A beta s might become internalized, either after t heir selective binding to cell-surface receptors or after membrane associat ion in consequence of their highly lipophilic nature, and induce free radic al generation and subsequent oxidative injury. Ca2+-mediated neurotoxic eve nts and generation of oxygen free radicals may indeed potentiate each other , or even converge to the same neurotoxic events, leading to cell death. 6. Neuroprotection against A beta toxicity was achieved by both pre- and po st-treatment with NMDA receptor channel antagonists. Moreover, direct radic al-scavengers, such as vitamin E or vitamin C, attenuated A beta toxicity w ith high efficacy. Interestingly, combined drug treatments did not necessar ily result in additive enhanced neuroprotection. 7. Similarly to the blockade of NMDA receptors, the neurotoxic action of A beta s could he markedly decreased by pharmacological manipulation of volta ge-dependent Ca2+-channels, serotonergic 1A or adenosine Al receptors, and by drugs eliciting membrane hyperpolarization or indirect blockade of Ca2+- mediated intracellular consequences of intracerebral A beta infusions. 8. A beta neurotoxicity might he dose-dependently modulated by trace metals . In spite of the fact that zinc (Zn) may act as a potent inhibitor of the NMDA receptor channel, high Zn doses accelerate A beta fibril formation, st abilize the beta-sheet conformation and thereby potentiate A beta neurotoxi city. Combined trace element supplementation with Se, Mn, or Mg, which prev ails over the expression of detoxifying enzymes or counteracts intracellula r elevations of Ca2+, may reduce the neurotoxic impact of A beta s. 9. Alterations in the regulatory functions of the hypothalamo-pituitary-adr enal axis may contribute significantly to neurodegenerative changes in the brain. Furthermore, AD patients exhibit substantially increased circadian l evels of steroid hormones, as well as baseline cortisol concentrations. In fact, a dose-dependent regulatory action of corticosterone on A beta or NMD A excitotoxicity has recently been demonstrated on MBN neurons, yielding a reversed bell-shaped dose-response profile. Furthermore, characteristic neu roprotective properties were postulated for estrogen both in vitro and in v ivo. 10. A novel approach in which 'beta-sheet breaker' peptide analogs are appl ied for the elimination of A beta fibrillogenesis/aggregation, or for the p revention of the direct binding of A beta s to possible selective cell-surf ace recognition sites (A beta receptors) provides promising in vivo tools f or the prevention of A beta toxicity.