Mass Histology to Quantify Neurodegeneration in &lt;em&gt;Drosophila&lt;/em&gt;

Sunderhaus, Elizabeth R.; Kretzschmar, Doris

doi:10.3791/54809

Cited by 25 publications

(21 citation statements)

References 39 publications

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“…To quantify light-induced neurodegeneration in the brain, we measured the average area of all vacuoles seen on sections of the brain as described previously. 37 Analyses were done double-blind, and statistical significance determined with unpaired t tests by using GraphPad Prism 6.…”

Section: Methodsmentioning

confidence: 99%

Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila

Nash¹,

Chow²,

Law³

et al. 2019

npj Aging Mech Dis

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Light is necessary for life, but prolonged exposure to artificial light is a matter of increasing health concern. Humans are exposed to increased amounts of light in the blue spectrum produced by light-emitting diodes (LEDs), which can interfere with normal sleep cycles. The LED technologies are relatively new; therefore, the long-term effects of exposure to blue light across the lifespan are not understood. We investigated the effects of light in the model organism, Drosophila melanogaster, and determined that flies maintained in daily cycles of 12-h blue LED and 12-h darkness had significantly reduced longevity compared with flies maintained in constant darkness or in white light with blue wavelengths blocked. Exposure of adult flies to 12 h of blue light per day accelerated aging phenotypes causing damage to retinal cells, brain neurodegeneration, and impaired locomotion. We report that brain damage and locomotor impairments do not depend on the degeneration in the retina, as these phenotypes were evident under blue light in flies with genetically ablated eyes. Blue light induces expression of stress-responsive genes in old flies but not in young, suggesting that cumulative light exposure acts as a stressor during aging. We also determined that several known blue-light-sensitive proteins are not acting in pathways mediating detrimental light effects. Our study reveals the unexpected effects of blue light on fly brain and establishes Drosophila as a model in which to investigate long-term effects of blue light at the cellular and organismal level.

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Section: Methodsmentioning

confidence: 99%

Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila

Nash¹,

Chow²,

Law³

et al. 2019

npj Aging Mech Dis

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“…Vacuoles were identified, counted, and their surface area measured using the magic wand tool in Photoshop before the genotype was revealed. For a detailed description of the method and analysis including a video see [50].…”

Section: Analysis Of Neurodegenerationmentioning

confidence: 99%

Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster

Long

Frame

Reardon

et al. 2020

Aging

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Lactate dehydrogenase (LDH) catalyzes the conversion of glycolysis-derived pyruvate to lactate. Lactate has been shown to play key roles in brain energetics and memory formation. However, lactate levels are elevated in aging and Alzheimer's disease patients, and it is not clear whether lactate plays protective or detrimental roles in these contexts. Here we show that Ldh transcript levels are elevated and cycle with diurnal rhythm in the heads of aged flies and this is associated with increased LDH protein, enzyme activity, and lactate concentrations. To understand the biological significance of increased Ldh gene expression, we genetically manipulated Ldh levels in adult neurons or glia. Overexpression of Ldh in both cell types caused a significant reduction in lifespan whereas Ldh down-regulation resulted in lifespan extension. Moreover, pan-neuronal overexpression of Ldh disrupted circadian locomotor activity rhythms and significantly increased brain neurodegeneration. In contrast, reduction of Ldh in neurons delayed age-dependent neurodegeneration. Thus, our unbiased genetic approach identified Ldh and lactate as potential modulators of aging and longevity in flies.

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“…Flies were obtained and aged as described for the phototaxis experiments. Paraffin sections for light microscopy were prepared and analyzed for vacuole formation as described in Botella et al (2003) and Sunderhaus and Kretzschmar (2016). Briefly, whole flies were fixed in Carnoy's solution and dehydrated in an ethanol series followed by incubation in methyl benzoate before embedding in paraffin.…”

Section: Tissue Sections and Vacuole Measurementsmentioning

confidence: 99%

Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons

et al. 2020

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A hallmark feature of Alzheimer's disease (AD) and other Tauopathies, like Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is the accumulation of neurofibrillary tangles composed of the microtubule-associated protein Tau. As in AD, symptoms of FTDP-17 include cognitive decline, neuronal degeneration, and disruptions of sleep patterns. However, mechanisms by which Tau may lead to these disturbances in sleep and activity patterns are unknown. To identify such mechanisms, we have generated novel Drosophila Tauopathy models by replacing endogenous fly dTau with normal human Tau (hTau) or the FTDP-17 causing hTau V337M mutation. This mutation is localized in one of the microtubule-binding domains of hTau and has a dominant effect. Analyzing heterozygous flies, we found that aged hTau V337M flies show neuronal degeneration and locomotion deficits when compared to wild type or hTau WT flies. Furthermore, hTau V337M flies are hyperactive and they show a fragmented sleep pattern. These changes in the sleep/activity pattern are accompanied by morphological changes in the projection pattern of the central pacemaker neurons. These neurons show daily fluctuations in their connectivity, whereby synapses are increased during the day and reduced during sleep. Synapse formation requires cytoskeletal changes that can be detected by the accumulation of the end-binding protein 1 (EB1) at the site of synapse formation. Whereas, hTau WT flies show the normal day/night changes in EB1 accumulation, hTau V337M flies do not show this fluctuation. This suggests that hTau V337M disrupts sleep patterns by interfering with the cytoskeletal changes that are required for the synaptic homeostasis of central pacemaker neurons.

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Mass Histology to Quantify Neurodegeneration in <em>Drosophila</em>

Cited by 25 publications

References 39 publications

Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila

Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila

Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster

Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons

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