Understanding the molecular basis of Alzheimer’s disease using a Caenorhabditis elegans model system

Abstract

Alzheimer’s disease (AD) is the major cause of dementia in the United States. At the cellular level, the brains of AD patients are characterized by extracellular dense plaques and intracellular neurofibrillary tangles whose major components are the β-amyloid peptide and tau, respectively. The β-amyloid peptide is a cleavage product of the amyloid precursor protein (APP); mutations in APP have been correlated with a small number of cases of familial Alzheimer’s disease. APP is the canonical member of the APP family, whose functions remain unclear. The nematode Caenorhabditis elegans, one of the premier genetic workhorses, is being used in a variety of ways to address the functions of APP and determine how the β-amyloid peptide and tau can induce toxicity. First, the function of the C. elegans APP-related gene, apl-1, is being examined. Although different organisms may use APP and related proteins, such as APL-1, in different functional contexts, the pathways in which they function and the molecules with which they interact are usually conserved. Second, components of the γ-secretase complex and their respective functions are being revealed through genetic analyses in C. elegans. Third, to address questions of toxicity, onset of degeneration, and protective mechanisms, different human β-amyloid peptide and tau variants are being introduced into C. elegans and the resultant transgenic lines examined. Here, we summarize how a simple system such as C. elegans can be used as a model to understand APP function and suppression of β-amyloid peptide and tau toxicity in higher organisms.

Modeling human neurodegenerative diseases in transgenic systems

“…In C. elegans there is a single APP-related gene, apl-1 (Ewald and Li 2010). Knockout of apl-1 causes lethality during early larval development while overexpression causes defects in brood size, movement and reduces viability.…”

“…C. elegans contains an active -secretase complex and like mammalian systems has multiple presenilins. Indeed work with the C. elegans presenilin SEL-12 provided the Wrst insights into the role of presenilins in mediating Notch signaling (Ewald and Li 2010). However, apl-1 lacks an A sequence and thus does not produce A peptide.…”

“…Early overt behavioral changes seen and strength of the phenotype generally correlated with the number of CAG repeats (-200) (Heng et al 2009;Levine et al 2004;Lin et al 2001;Raymond et al 2011;Shelbourne et al 1999;Wheeler et al 2000;White et al 1997 (Bugos et al 2009;Clarke et al 2007;Echeverria et al 2004;Agca et al 2008;Flood et al 2009;Folkesson et al 2007;Liu et al 2008a;Ruiz-Opazo et al 2004 of A 3-42 after cleavage (Link 1995). Expression of this human A 42 minigene in muscle cells resulted in progressive paralysis and staining of muscle cells with a human A 42 speciWc antibody revealed A 42 deposits that reacted with Congo red and thioXavin S. Ultrastructural studies, however, revealed that the deposits were intracytoplasmic rather than extracellular as are amyloid plaques found in AD (Ewald and Li 2010). Pan-neuronal expression of human A 42 has also been associated with amyloid deposits and deWcits in odorant preference-associated learning behavior, serotonin-controlled behaviors, experiencedependent learning and egg laying behavior (Dosanjh et al 2010).…”

“…Pan-neuronal expression of human A 42 has also been associated with amyloid deposits and deWcits in odorant preference-associated learning behavior, serotonin-controlled behaviors, experiencedependent learning and egg laying behavior (Dosanjh et al 2010). Transgenic C. elegans has also been used to investigate how speciWc residues within human A aVect Wbril formation (Ewald and Li 2010). Models such as those developed in C. elegans may be questioned for their reliance on the isolated overexpression of a non-native protein that is not naturally processed.…”

Die Chemie und der Wurm: Caenorhabditis elegans als Plattform für das Zusammenführen von chemischer und biologischer Forschung

“…Diese Strategie ermöglichte die Studie von Analogen zahlreicher menschlicher neurodegenerativer Krankheiten in C. elegans, einschließlich der Alzheimer-Krankheit [123][124][125] (AD) und Chorea Huntington [126,127] (HD). Im Menschen ist die Alzheimer-Krankheit durch die Aggregation von b-Amyloidpeptid(Ab)-haltigen Proteinen zu Plaques oder Fibrillen im Gehirn des Patienten sowie durch schwere oxidative Schäden des Hirngewebes charakterisiert.…”