Simple model systems: a challenge for Alzheimer's disease

Abstract

The success of biomedical researches has led to improvement in human health and increased life expectancy. An unexpected consequence has been an increase of age-related diseases and, in particular, neurodegenerative diseases. These disorders are generally late onset and exhibit complex pathologies including memory loss, cognitive defects, movement disorders and death. Here, it is described as the use of simple animal models such as worms, fishes, flies, Ascidians and sea urchins, have facilitated the understanding of several biochemical mechanisms underlying Alzheimer's disease (AD), one of the most diffuse neurodegenerative pathologies. The discovery of specific genes and proteins associated with AD, and the development of new technologies for the production of transgenic animals, has helped researchers to overcome the lack of natural models. Moreover, simple model systems of AD have been utilized to obtain key information for evaluating potential therapeutic interventions and for testing efficacy of putative neuroprotective compounds.

Figure 1

The two pathological hallmarks of AD are extracellular plaques and intracellular tangles. Plaques are formed mostly from the deposition of amyloid beta (Ab) a peptide derived from amyloid precursor protein (APP). The metabolic processing of APP that results in Ab formation requires two enzymatic cleavage events, a b-secretase cleavage by the aspartyl protease beta-site APP-cleaving enzyme (BACE) and a g-secretase cleavage dependent on presenilin. Single beta-amyloid peptides, after misfolding, can aggregate and form fibrils and successively plaques. Filamentous neurofibrillary tangles (NTF) are formed from paired helical filaments composed of hyperphosphorylated tau protein, a microtubule-associated protein.

Figure 2

Simple model systems as zebrafish, Drosophila, C. elegans, Ascidian and sea urchin have been used to study neurodegeneration.