Pathological Peptide Folding in Alzheimers Disease and Other Conformational Disorders

Author(s): Peter P. Mager, Botond Penke, Regina Walter, Tibor Harkany, Wolfgang Hartig.

Journal Name: Current Medicinal Chemistry

Volume 9 , Issue 19 , 2002

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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

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Article Details

VOLUME: 9
ISSUE: 19
Year: 2002
Page: [1763 - 1780]
Pages: 18
DOI: 10.2174/0929867023369169
Price: $58

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