Abstract
Alzheimer’s disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant Aβ42 gene. We identified 3093 proteins from flies that were induced to express Aβ42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by Aβ42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems.
Highlights
Alzheimer’s disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments
Oxidised proteins accumulate at early stages in AD brain, probably as a result of mitochondrial ROS p roduction[18], and redox proteomic approaches suggest that enzymes involved in glucose metabolism are oxidised in mild cognitive impairment and A D19,20
To understand how the brain proteome is affected as Aβ42 toxicity progresses, fly brains were dissected from healthy and Aβ42 flies at 5, 19, 31 and 46 days, and at 54 and 80 days for healthy controls, analysed by labelfree quantitative IM-DIA-MS (Fig. 1c, Supplementary Data 1). 1854 proteins were identified in both healthy and Aβ42 fly brain from a total of 3093 proteins (Fig. 1d), which is typical for recent fly proteomics studies[25,26]
Summary
Alzheimer’s disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Plaques are extracellular aggregates of amyloid beta (Aβ)[2], whereas neurofibrillary tangles are intraneuronal aggregates of hyperphosphorylated t au[3,4] In addition to these hallmarks, the AD brain experiences many other changes, including metabolic and oxidative d ysregulation[5,6], DNA damage[7], cell cycle re-entry[8], axon loss[9] and, eventually, neuronal death[6,10]. Comparison of proteomic analyses of post-mortem human brains have further revealed an increase in metabolic processes and reduction in synaptic function in A D17. Oxidised proteins accumulate at early stages in AD brain, probably as a result of mitochondrial ROS p roduction[18], and redox proteomic approaches suggest that enzymes involved in glucose metabolism are oxidised in mild cognitive impairment and A D19,20. Post-mortem studies reflect the end-stage of disease and, do not facilitate measurement of dynamic alterations in proteins as AD progresses
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