Role of longevity on tau and amyloid beta-induced cell toxicity and unfold protein response in drosophila melanogaster alzheimers disease model

Javad Amini,1 Nima sanadgol,2 Mohsen shahriari,3 Mohammd hadadi,4 Naser sanchooli,5,*

1. master student of university zabol
2. department of biology, faculty of sience, university of zabol, zabol. iran
3. department of environment, faculty of natural resources, university of zabol, zabol. iran
4. assistant professor department of bioligy, university of zabol, zabol. iran
5. assistant professor of zoology department of biology faculyt sience university of zabol

Abstract

Introduction

Aging is one of the most important factor in the development of alzheimers disease (ad). the important pathologic proteins involved in the development of ad are amyloid beta (aβ) and tau. although the accumulation of unfolded proteins in ad has been proven, and the role of endoplasmic network in the resolving these proteins has been identified, the effect of longevity on efficiency of unfold protein response (upr) are under debates. one key question of debate, however, is which of these pathologies appears first and hence is upstream in the pathocascade. in this study we compare the effects of aβ and tau-induced cell toxicity and unfold protein response in an age-dependent manner in drosophila melanogaster (dm) ad model.

Methods

The strains usa-tau r406w and usa-aβ, the eye (gmr-gal4), ok107- gal4, and pan-neural (elav-gal4) driver strains, were obtained from the bloomington drosophila stock center (flystocks.bio.indiana.edu). homozygous virgin females ok107-gal4 were mated with either males bearing uas-aβ constructs (for aβ expression in brain neurons) or males bearing uas-tau constructs (for tau expression in brain neurons), and the progeny was maintained at 270c. for transgene expression in the eye, homozygous females gmr-gal4 uas-aβ were crossed with males carrying the desired constructs and the progeny was maintained at 27.50c. for histological study of retinas, paraffin-embedded heads of 10, 20 or 30-day-old flies after progeny were sectioned at 1 mm and analyzed. at mentioned time points flies were also unseized with co2, and total rna was isolated from 45 fly heads, and cdnas were prepared. expression of tau, aβ, atf6, atf4 and xbp1 in brain of flies were evaluated via real-time pcr using specific primer sets.

Results

As predicted, aβ and tau over expressed in the brain neurons and constantly induced cell toxicity and ad phenotypes in flies according to behavior and histological assessments. surprisingly, with age increasing, the expression of important upr markers atf6, atf4 and xbp1 were significantly increased in tau r406w model in compare with aβ model in an age dependent manner

Conclusion

Both extracellular amyloid plaques and intra-neuronal neurofibrillary tangles are highly insoluble and densely packed filaments. the soluble building blocks of these structures are amyloid-β (aβ) peptides for plaques and tau for tangles. amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. the ability of therapeutic interventions targeting just one of these molecules, to successfully neutralize the toxicity of the other, needs to be ascertained to improve current therapeutic strategies, for the treatment of ad. consistent with our results, during longevity aβ exerts more toxic effects via activation of ups pathway than tau and we propose that anti-aβ therapies could effectively reduce ad pathology in aged individuals

Keywords

Alzheimers disease, unfolded protein response, tau, beta amyloid, drosophila melanogaster