Pathological peptide folding in Alzheimer's disease and other conformational disorders

Peter P. Mager, B. Penke, Regina Walter, Tibor Harkany, Wolfgang Härtig

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Main neuropathological hallmarks of Alzheimer's 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 β-amyloid peptides (Aβ), containing up to 43 amino acid residues derived from the β-amyloid precursor protein. Such Aβ-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, α-helical, lipophilic, antigenic folding domain of the Aβ-peptide loop is a promising molecular target of β-sheet breakers that thus prevent the polymerization of Aβ into aggregates. It seems that di- and tetramers of Aβ-peptides have a β-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structure-activity relationships of peptidomimetic β-sheet breakers. The anti-aggregatory potency of β-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 β-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 β-sheet conformation and thus abrogating their effects in a broad variety of disorders.

Original languageEnglish
Pages (from-to)1763-1780
Number of pages18
JournalCurrent Medicinal Chemistry
Volume9
Issue number19
Publication statusPublished - 2002

Fingerprint

Alzheimer Disease
Peptides
Conformations
Amyloid
Peptidomimetics
tau Proteins
Neurofibrillary Tangles
Prion Diseases
Amyloid beta-Protein Precursor
Amyloid Plaques
Amyloidosis
Drug therapy
Structure-Activity Relationship
Mechanics
Static Electricity
Molecular mechanics
Polymerization
Neurodegenerative Diseases
Cholinergic Agents
Prions

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Mager, P. P., Penke, B., Walter, R., Harkany, T., & Härtig, W. (2002). Pathological peptide folding in Alzheimer's disease and other conformational disorders. Current Medicinal Chemistry, 9(19), 1763-1780.

Pathological peptide folding in Alzheimer's disease and other conformational disorders. / Mager, Peter P.; Penke, B.; Walter, Regina; Harkany, Tibor; Härtig, Wolfgang.

In: Current Medicinal Chemistry, Vol. 9, No. 19, 2002, p. 1763-1780.

Research output: Contribution to journalArticle

Mager, PP, Penke, B, Walter, R, Harkany, T & Härtig, W 2002, 'Pathological peptide folding in Alzheimer's disease and other conformational disorders', Current Medicinal Chemistry, vol. 9, no. 19, pp. 1763-1780.
Mager, Peter P. ; Penke, B. ; Walter, Regina ; Harkany, Tibor ; Härtig, Wolfgang. / Pathological peptide folding in Alzheimer's disease and other conformational disorders. In: Current Medicinal Chemistry. 2002 ; Vol. 9, No. 19. pp. 1763-1780.
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