Expression of Alzheimer-Like Pathological Human Tau Induces a Behavioral Motor and Olfactory Learning Deficit in Drosophila melanogaster

Beharry, Cindy; Alaniz, Maria Eugenia; Alonso, Alejandra

doi:10.3233/jad-130617

Cited by 34 publications

(33 citation statements)

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“…We have shown that phosphorylation of tau is suffi cient to promote tau self-assembly into fi laments [29] and that phosphorylation at Ser 199 and 262 and Thr 212 and 231 is sufficient to convert tau into an D-like protein in cells [101] and in vivo in transgenic Drosophila [126] . On the basis of our results and the evidence reviewed here, we propose that the hyperphosphorylation of tau leads to neurodegeneration through microtubule disruption and the consequent decreases in neurotransmission a n d a x o p l a s m i c t r a n s p o r t ( F i g .…”

Section: Discussionmentioning

confidence: 95%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

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Section: Discussionmentioning

confidence: 95%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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“…Several disease-linked mutations in the Tau gene affect correct splicing of its MT binding sites, thus enhancing abnormal phosphorylation and detachment of the protein. Both steps are believed to be crucial in the process of forming paired helical filaments and higher order neurofibrillary tangles [65,66]. …”

Section: Introductionmentioning

confidence: 99%

Drosophila melanogaster as a model organism for Alzheimer’s disease

Prüßing

Voigt

Schulz

2013

Mol Neurodegeneration

201

116

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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.

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“…This neuronal loss and synaptic degeneration are caused by the presence of plaques and tangles [85]. Consistently, several studies showed that Drosophila AD models are also impaired in learning and memory [11, 86–88], which makes Drosophila a useful model of the defective brain functions of AD.…”

Section: Drosophila As a Model System For Neurodegenerative Diseasesmentioning

confidence: 88%

Evaluation of Traditional Medicines for Neurodegenerative Diseases Using Drosophila Models

Lee

Bang

Lee

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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Drosophila is one of the oldest and most powerful genetic models and has led to novel insights into a variety of biological processes. Recently, Drosophila has emerged as a model system to study human diseases, including several important neurodegenerative diseases. Because of the genomic similarity between Drosophila and humans, Drosophila neurodegenerative disease models exhibit a variety of human-disease-like phenotypes, facilitating fast and cost-effective in vivo genetic modifier screening and drug evaluation. Using these models, many disease-associated genetic factors have been identified, leading to the identification of compelling drug candidates. Recently, the safety and efficacy of traditional medicines for human diseases have been evaluated in various animal disease models. Despite the advantages of the Drosophila model, its usage in the evaluation of traditional medicines is only nascent. Here, we introduce the Drosophila model for neurodegenerative diseases and some examples demonstrating the successful application of Drosophila models in the evaluation of traditional medicines.

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Expression of Alzheimer-Like Pathological Human Tau Induces a Behavioral Motor and Olfactory Learning Deficit in Drosophila melanogaster

Cited by 34 publications

References 72 publications

Tau-induced neurodegeneration: mechanisms and targets

Tau-induced neurodegeneration: mechanisms and targets

Drosophila melanogaster as a model organism for Alzheimer’s disease

Evaluation of Traditional Medicines for Neurodegenerative Diseases Using Drosophila Models

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