Abstract:
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia which currently affects over 40 million people worldwide. Pathologically, AD is characterized by two important hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles, made up predominantly by proteins known as β-amyloid (Aβ) and hyperphosphorylated Tau, respectively. Mutations in the Aβ precursor protein (APP) and two proteins involved in Aβ production (presenilin 1 and 2, components of the γ-secretase complex) cause heritable early onset AD, typically prior to 65 years old. However, the majority of AD cases occur in people over the age of 65 due to multifactorial causes. Despite over two decades of intensive research, the physiological roles and mechanistic contribution of APP and Aβ to late onset AD still remain elusive. Caenorhabditis elegans is emerging as a powerful tool in the research of neurodegenerative disorders, complementing the traditional mammalian systems with straight forward genetics, simplicity of their neuronal network, and short generation time. Previous studies have shown that transgenic C. elegans overexpressing human Aβ in muscle cells develop intracellular Aβ aggregation and a progressive paralysis, while those expressing Aβ in neurons reveal behavioural deficits. To further understand Aβ, APP and to model AD related physiology as closely as possible, transgenic C. elegans strains which express full-length human APP and human β-secretase, an enzyme responsible for the first step of Aβ production, were made. The transgenes were driven by appropriate promoters and fluorescent tagged fusion proteins expressing lines were also developed. The transgenic animals displayed phenotypical changes, associated with the presence of the transgenes.