Abstract
Main neuropathological hallmarks of Alzheimers disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble ß-amyloid peptides (Aß), containing up to 43 amino acid residues derived from the ß-amyloid precursor protein. Such Aß-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, α-helical, lipophilic, antigenic folding domain of the Aßpeptide loop is a promising molecular target of ß-sheet breakers that thus prevent the polymerization of Aß into aggregates. It seems that di- and tetramers of Aß-peptides have a ß-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structureactivity relationships of peptidomimetic ß-sheet breakers. The anti-aggregatory potency of ß-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic α-helix / random-coils to ß-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from α- helical / random coil to ß-sheet conformation and thus abrogating their effects in a broad variety of disorders.
Keywords: Pathological Peptide, Alzheimers Disease, Gasteiger-molecular
Current Medicinal Chemistry
Title: Pathological Peptide Folding in Alzheimers Disease and Other Conformational Disorders
Volume: 9 Issue: 19
Author(s): Peter P. Mager, Botond Penke, Regina Walter, Tibor Harkany and Wolfgang Hartig
Affiliation:
Keywords: Pathological Peptide, Alzheimers Disease, Gasteiger-molecular
Abstract: Main neuropathological hallmarks of Alzheimers disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble ß-amyloid peptides (Aß), containing up to 43 amino acid residues derived from the ß-amyloid precursor protein. Such Aß-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, α-helical, lipophilic, antigenic folding domain of the Aßpeptide loop is a promising molecular target of ß-sheet breakers that thus prevent the polymerization of Aß into aggregates. It seems that di- and tetramers of Aß-peptides have a ß-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structureactivity relationships of peptidomimetic ß-sheet breakers. The anti-aggregatory potency of ß-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic α-helix / random-coils to ß-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from α- helical / random coil to ß-sheet conformation and thus abrogating their effects in a broad variety of disorders.
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Cite this article as:
Mager P. Peter, Penke Botond, Walter Regina, Harkany Tibor and Hartig Wolfgang, Pathological Peptide Folding in Alzheimers Disease and Other Conformational Disorders, Current Medicinal Chemistry 2002; 9 (19) . https://dx.doi.org/10.2174/0929867023369169
DOI https://dx.doi.org/10.2174/0929867023369169 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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