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 beta-amyloid peptide and tau, respectively. The beta-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 beta-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 gamma-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 beta-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 beta-amyloid peptide and tau toxicity in higher organisms.

Fig. 1

Schematic of the processing pathways of human amyloid precursor protein (APP; a) and its C. elegans ortholog APL-1 (b). a) APP undergoes two processing pathways, α/γ-secretase or β/γ-secretase, to produce sAPPα/AICD or sAPPβ/AICD, respectively. Only the β/γ-secretase pathway produces the amyloid peptide (Aβ). α-Secretase corresponds to ADAM17/TACE, β-secretase to BACE. b) In C. elegans, APL-1 undergoes at least one processing pathway to produce sAPL-1 and presumably AICD. α-Secretase may correspond to SUP-17, ADAM10, or ADM-4 ADAM17/TACE. No β-secretase activity has been described in C. elegans. NCT/APH-2 nicastrin; conserved domains: cysteine-rich E1 and acidic residue-rich E2 domain, AICD APP or APL-1 intracellular cytoplasmic domain.

Fig. 2

Expression of an APL-1::GFP translational fusion in C. elegans. APL-1::GFP is seen in multiple cell types, including neurons and processes (arrowheads), glial sheath cells (arrow), and muscle cells (chevron). Anterior head region shown, ventral side is down. Scale bar = 10 μm