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Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people and currently lacking available disease-modifying treatments. Appropriate disease models are necessary to investigate disease mechanisms and potential treatments. Drosophila melanogaster models of AD include the A? fly model and the A?PP-BACE1 fly model. In the A? fly model, the A? peptide is fused to a secretion sequence and directly overexpressed. In the A?PP-BACE1 model, human A?PP and human BACE1 are expressed in the fly, resulting in in vivo production of A? peptides and other A?PP cleavage products. Although these two models have been used for almost two decades, the underlying mechanisms resulting in neurodegeneration are not yet clearly understood. In this study, we have characterized toxic mechanisms in these two AD fly models. We detected neuronal cell death and increased protein carbonylation (indicative of oxidative stress) in both AD fly models. In the A? fly model, this correlates with high A?1-42 levels and down-regulation of the levels of mRNA encoding lysosomal-associated membrane protein 1, lamp1 (a lysosomal marker), while in the A?PP-BACE1 fly model, neuronal cell death correlates with low A?1-42 levels, up-regulation of lamp1 mRNA levels and increased levels of C-terminal fragments. In addition, a significant amount of A?PP/A? antibody (4G8)-positive species, located close to the endosomal marker rab5, was detected in the A?PP-BACE1 model. Taken together, this study highlights the similarities and differences in the toxic mechanisms which result in neuronal death in two different AD fly models. Such information is important to consider when utilizing these models to study AD pathogenesis or screening for potential treatments.

SUBMITTER: Bergkvist L

PROVIDER: S-EPMC7050262 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease.

Bergkvist Liza L Du Zhen Z Elovsson Greta G Appelqvist Hanna H Itzhaki Laura S LS Kumita Janet R JR Kågedal Katarina K Brorsson Ann-Christin AC

FEBS open bio 20200122 3

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people and currently lacking available disease-modifying treatments. Appropriate disease models are necessary to investigate disease mechanisms and potential treatments. Drosophila melanogaster models of AD include the Aβ fly model and the AβPP-BACE1 fly model. In the Aβ fly model, the Aβ peptide is fused to a secretion sequence and directly overexpressed. In the AβPP-BACE1 model, human AβPP and human BACE1 are e ...[more]

PMID: 31823504

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Project description:BACKGROUND: High-throughput profiling of human tissues typically yield as results the gene lists comprised of a mix of relevant molecular entities with multiple false positives that obstruct the translation of such results into mechanistic hypotheses. From general probabilistic considerations, gene lists distilled for the mechanistically relevant components can be far more useful for subsequent experimental design or data interpretation. RESULTS: The input candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subsets of the same experiments and across different experiments and platforms. The cut-offs were established empirically through ontological and semantic enrichment; resultant shortened gene list was re-expanded by Ingenuity Pathway Assistant tool. The resulting sub-networks provided the basis for generating mechanistic hypotheses that were partially validated by literature search. This approach differs from previous consistency-based studies in that the cut-off on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The gene list distilled by this analytic technique and its network representation were termed Compact Disease Model (CDM). Here we present the CDM signature for the study of early-stage Alzheimer's disease. The integrated analysis of this gene signature allowed us to identify the protein traffic vesicles as prominent players in the pathogenesis of Alzheimer's. Considering the distances and complexity of protein trafficking in neurons, it is plausible that spontaneous protein misfolding along with a shortage of growth stimulation result in neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis have been discussed, with an emphasis on the protective effects of AT-1 mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Alignment with emerging literature confirmed many predictions derived from early-stage Alzheimer's disease' CDM. CONCLUSIONS: A flexible approach for high-throughput data analysis, the Compact Disease Model generation, allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses.

Dataset Information

Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease.

Publications

Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease.

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