Inhibition of Alzheimer β-Fibrillogenesis by Melatonin

Abstract

It is generally postulated that the amyloid ␤ protein (A␤) plays a central role in the progressive neurodegeneration observed in Alzheimer's disease. Important pathologic properties of this protein, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of A␤ to form ␤-sheet structures or amyloid fibrils. We report that melatonin, a hormone recently found to protect neurons against A␤ toxicity, interacts with A␤1-40 and A␤1-42 and inhibits the progressive formation of ␤-sheets and amyloid fibrils. These interactions between melatonin and the amyloid peptides were demonstrated by circular dichroism and electron microscopy for A␤1-40 and A␤1-42 and by nuclear magnetic resonance spectroscopy for A␤1-40. Inhibition of ␤-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.Most of the recent advances in Alzheimer's disease (AD) 1 stem from the study of a 40 -42-amino acid peptide called the amyloid ␤ protein (A␤) as the essential pathologic marker of this disorder (1, 2). In brains afflicted with AD, deposits of A␤ in the form amyloid fibrils are widespread within senile plaques and in cerebral and meningeal blood vessels (3, 4). Interestingly, A␤ is normally produced as a soluble peptide (5-8), and whether this form of A␤ is the immediate precursor of the amyloid deposits is still unknown. Synthetic peptides homologous to A␤1-40 and A␤1-42, however, undergo spontaneous rearrangements of their initial secondary structure, generating oligomeric and polymeric species with higher content of ␤-sheets (9 -15). Such changes are either promoted or inhibited by numerous factors (9, 14, 16 -22).The secondary structure determines several important properties of A␤ that may be relevant to the pathogenesis of AD.First, it has been demonstrated that the amyloid peptide is neurotoxic (23)(24)(25) and that this characteristic is associated with formation of ␤-sheets (15, 26 -31) or amyloid fibrils (31). Second, the ability of A␤ to form fibrils is directly correlated with the content of ␤-sheet structures adopted by the peptide (32). In this regard, it has been proposed that peptides with high contents of ␤-sheets can act as seeds for nucleation and fibril formation (33, 34). Finally, A␤ peptides with high contents of ␤-sheets become partially resistant to proteolytic degradation, and this may be a crucial mechanism in amyloid deposition (35). Such protease resistance and insolubility features, shared by all known forms of amyloidoses, prevent amyloid removal from tissue deposits. Thus, by preventing the formation of ␤-sheets one could not only reduce neurotoxicity but also facilitate clearance of A␤ via increased proteolytic d...

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

“…Tomiyama et al (1996) suggested that Rif binds to Aß by hydrophobic interactions between its lipophilic ansa chain and the hydrophobic region of Aß, thus blocking associations between Aß molecules leading to fAß formation. The anti-amyloidogenic and fibril-destabilizing activity of tetracycline (Tc), small-molecule anionic sulphonates or sulphates, melatonin, ß-sheet breaker peptides (iAß5) and nicotine may also be related to the propensity to bind to the specific sites of Aß (Kisilevsky et al 1995;Soto et al 1996;Pappolla et al 1998;Forloni et al 2001;Zeng et al 2001). Thus, it may be reasonable to consider that NSAIDs could exhibit their anti-amyloidogenic and fibril-destabilizing effects by directly binding to Aßs and/or fAßs.…”

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

“…However, in recent experiments, the incubation of Ab in the presence of Cu 21 resulted in decreased Ab fibril formation, although no explanation for these processes at the atomistic level has been provided. [11][12][13] Although several theoretical and experimental studies have been conducted with the aim of explaining the interaction of Cu 21 and Ab, several contradictory results have emerged. 16 These contradictions might be explained by the different experimental conditions used by different research groups, which have included different pH values, 23 21 , Ab suffered conformational changes.…”

“…7 In addition, numerous compounds have been found to reduce Ab 1242 aggregation in vitro. 11,12 However, the usefulness of these compounds as inhibitors of Ab 1242 aggregation remains speculative due to their lack of specificity and/or unknown mechanism of action. For example, galanthamine (Reminil V R ; AChE inhibitor) has been recently demonstrated to interact with soluble Ab to inhibit the formation of the toxic oligomeric species in a concentration-dependent manner, but its mechanism of interaction has not been well established.…”

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

“…6 As Ab is toxic to neurons, 7 the main targets for therapeutic intervention of the Ab cascade include the inhibition of Ab production, the inhibition of Ab aggregation and fibril formation, in addition to the inhibition of the consequent inflammatory responses caused by the Ab deposition. In this context, several substances are known to inhibit Ab fibrillogenesis in vitro, including laminin, 6,8 melatonin, 9 nordihydroguaiaretic acid, 10 polyphenols, 11 site-directed monoclonal antibodies, 12 a1-antichymotrypsin, 13 Ginkgo biloba extract, 14 type IV collagen 15 and b-sheet breaker peptides. 16 Nevertheless, an effective therapeutic approach that interferes directly with the neurodegenerative process in AD is eagerly awaited.…”