Drosophila Models of Alzheimer's Amyloidosis: The Challenge of Dissecting the Complex Mechanisms of Toxicity of Amyloid-β 42

Issue title: Animal Models of Alzheimer's Disease: Therapeutic Implications

Guest editors: Diana Woodruff-Pak

Article type: Research Article

Authors: Iijima, Koichi^{a; *} | Iijima-Ando, Kanae^{b; *}

Affiliations: [a] Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA | [b] Laboratory of Neurogenetics and Pathobiology, Farber Institute for Neurosciences, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence: [*] Corresponding author: Koichi Iijima, 900 Walnut Street, JHN410, Philadelphia, PA19107, USA. Tel.: +1 215 9554 546; Fax: +1 215 955 4949; E-mail: [email protected], or Kanae Iijima-Ando, 900 Walnut Street, JHN410, Philadelphia, PA19107, USA. Tel.: +1 215 503 9897; Fax: +1 215 955 4949; E-mail: [email protected].

Abstract: Alzheimer's disease (AD) is the most common form of senile dementia, and a cure is desperately needed. The amyloid-β42 (Aβ42) has been suggested to play a central role in the pathogenesis of AD. However, the mechanism by which Aβ42 causes AD remains unclear. To understand the pathogenesis and to develop therapeutic avenues, it is crucial to generate animal models of AD in genetically tractable organisms. Drosophila is a well-established model system for which abundant genetic tools are available. Moreover, its well organized brain permits the study of complex behaviors such as learning and memory. We have established transgenic flies that express human Aβ42 in the nervous system. These flies developed age-dependent short-term memory impairment and neurodegeneration. In this review, we will first describe transgenic Aβ42 fly models and discuss the unique features of this system compared to mouse AD models. Secondly, we will discuss the usage of the fly models to evaluate currently proposed therapeutic strategies. Thirdly, we will briefly review the results of a genetic screen for modifiers of Aβ42 toxicity in the fly model. Finally, we will discuss how to dissect the complex mechanisms of Aβ42 toxicity focusing on its aggregation propensity using the fly model system.

Keywords: Alzheimer disease, amyloid-β42, animal model, Drosophila, genome-wide screen, learning and memory, neprilysin, neurodegenerative disease, protein misfolding

DOI: 10.3233/JAD-2008-15402

Journal: Journal of Alzheimer's Disease, vol. 15, no. 4, pp. 523-540, 2008