Drosophila melanogaster as a model organism for Alzheimer’s disease

Abstract

Drosophila melanogaster provides an important resource for in vivo modifier screens of neurodegenerative diseases. To study the underlying pathogenesis of Alzheimer’s disease, fly models that address Tau or amyloid toxicity have been developed. Overexpression of human wild-type or mutant Tau causes age-dependent neurodegeneration, axonal transport defects and early death. Large-scale screens utilizing a neurodegenerative phenotype induced by eye-specific overexpression of human Tau have identified several kinases and phosphatases, apoptotic regulators and cytoskeleton proteins as determinants of Tau toxicity in vivo. The APP ortholog of Drosophila (dAPPl) shares the characteristic domains with vertebrate APP family members, but does not contain the human Aβ42 domain. To circumvent this drawback, researches have developed strategies by either direct secretion of human Aβ42 or triple transgenic flies expressing human APP, β-secretase and Drosophila γ-secretase presenilin (dPsn). Here, we provide a brief overview of how fly models of AD have contributed to our knowledge of the pathomechanisms of disease.

Drosophila melanogaster: Deciphering Alzheimer's Disease

“…Despite this, Congo Red which blocks Aβ oligomerisation was able to rescue the shortened lifespan. Again, the data showed that intracellular Aβ and extracellular soluble Aβ cause neurodegeneration (14). This debunking of the common consensus whereby Aβ40 and Aβ42 peptides are the root behind toxicity in AD pathogenesis has also been shown in previous studies utilising other animal models (57,58).…”

“…The peptide binds to other Aβ peptides and accumulate into fibrils. It should be noted that the three main genes posing risk elements for EOFAD are part of the amyloid pathology, namely APP, Presenilin 1 and Presenilin 2 (14).…”

“…Thus, there is no production of the gene in wild type Drosophila (14). In addition, Drosophila do not possess the human beta-secretase (BACE) enzyme.…”

“…The expression is also parallel to signal peptide levels generated by amyloidogenic processing of APP, therefore erasing any factors from APP processing. Concisely, this system provides a pioneering method to directly assess the toxicity of either Aβ42 or Aβ40 separately (14,51,55).…”

<i>Drosophila</i> Ogg1 is required to suppress 8-oxo-guanine accumulation following oxidative stress

“…Drosophila melanogaster has been the subject of intensive genetic analyses investigating the role of genes implicated in various biological phenomena (Pandey and Nichols, 2011;Prüßing et al, 2013). Drosophila also possesses an Ogg1 ortholog, which excises 8-oxo-guanines from γ-irradiated DNA in vitro.…”