Die Alzheimer‐Demenz: von der Pathologie zu therapeutischen Ansätzen

Abstract

Die gegenwärtigen Strategien zur Entwicklung von Alzheimer‐Therapien sind breit gefächert. Ein verstärktes Augenmerk gilt der Suche nach Hemmstoffen (siehe Bild für zwei Beispiele) der proteolytischen Enzyme β‐ und γ‐Secretase, die die Spaltung des Amyloid‐Vorläuferproteins in Amyloid‐β‐Peptide inhibieren, aus denen die krankheitstypischen Plaque‐Ablagerungen im Gehirn von Alzheimer‐Patienten entstehen.magnified imageDie Forschungen über Altersdemenz und die Alzheimersche Krankheit umfassen ein sehr breites Feld wissenschaftlicher Aktivitäten. So wurden etwa bei der letztjährigen internationalen Tagung der Alzheimer‐Gesellschaft (ICAD 2008 in Chicago) mehr als 2200 Einzelbeiträge präsentiert. Ziel dieses Aufsatzes ist es, einen zusammenhängenden Überblick über das Gebiet zu präsentieren und die wichtigsten Themen und Forschungstrends aufzuzeigen. Die Ausführungen beginnen mit einer Diskussion von Verhaltensabweichungen und sichtbaren pathologischen Befunden, bevor dann auf die molekularen Details der Pathologie eingegangen wird. Besonderes Augenmerk gilt der “Amyloidhypothese” der Alzheimer‐Krankheit, da sie das theoretische Fundament für die meisten der in der Entwicklung befindlichen therapeutischen Konzepte bildet.

Inhibition of Beta‐Amyloid Peptide Aggregation by Multifunctional Carbazole‐Based Fluorophores

“…[1] It is commonly accepted that betaamyloid (Ab) peptides of 40 and 42 residues formed from the cleavage of amyloid precursor protein play a key role in AD pathogenesis where the aggregation of monomeric Ab peptides to insoluble plaque-associated amyloid fibrils via soluble oligomeric intermediates would induce a cascade of events that eventually lead to the death of neuronal cells. [2] The fibrillogenesis of Ab is a two-phase process, involving nucleation and elongation phases, during which the Ab peptides undergo conformational transition from predominantly unstructured form to a b-sheet-rich structure which stacks along the long axis of the fibrils through end-to-end annealing and the lateral association mechanism proposed by Walsh and co-workers.…”

Structural Basis of β‐Amyloid‐Dependent Synaptic Dysfunctions

“…[19] The presently documented role of the peptide N-terminus in stabilizing Ab oligomers argues that this sequence region could be instrumental for AD. For example, this region has been used for AD immunotherapy, [22] whereas Nterminal pyroglutamate modifications or allelic mutations were shown to promote the onset of AD and Ab aggregation in vitro, [17] and evidence for N-terminal stability in Ab fibrils or peptide has been provided by biochemical analysis, cryo electron microscopy and molecular modelling. [20,21] Indeed, LTP-dependent memory deficits can be ameliorated with BSB peptide fragments derived from the Ab N-terminus.…”

Sulfonamides as multifunctional agents for Alzheimer’s disease

“…In all 26 sulfonamides have been synthesized and tested in a variety of assays related to AD pathology and neurochemical abnormalities of the disease. The compounds can be categorized into three groups: commercially available, sulfonamides with limited length and size (1)(2)(3)(4)(5); cyclic sulfonamides (6)(7)(8)(9)(10)(11)(12) and openchain sulfonamides (13-26) with a head and tail group that was linked with a long chain in order to span the active center of the cholinesterases. The structure-activity relationship in the different assays reveals significant information for future design.…”

“…The small commercial sulfonamides and saccharin derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) showed moderate inhibition (up to 54%, except 11) of oligomers while the long chain linker containing sulfonamides (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were generally oligomer formation promoters. Interestingly, 27 and 28 showed 50-100% inhibition of oligomer formation.…”

“…1,2 In response to the pressing need of an aging population several treatment strategies have been explored. [3][4][5][6][7] The most common approaches are related to the cholinerg 8 and amyloid cascade hypotheses. 9 The formation of Ab peptide self-assemblies (oligomers and fibrils) and their neurotoxic effects are believed to be major contributors to the development of AD.…”