Basic Science and Pathogenesis.

Background: In Alzheimer's disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations.

Method: We have functionally dissected 30 AD-associated gene coexpression modules using a cross-species strategy in Drosophila melanogaster models. First, integrating longitudinal RNA-sequencing and fly behavioral phenotyping, we interrogated unique and shared transcriptional responses to amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and/or aging, along with potential links to progressive neuronal dysfunction. In order to confirm causal modules and pinpoint AD network drivers, we next performed systematic in vivo genetic manipulations of 357 conserved, prioritized targets to identify modifiers of Aβ- and/or tau-induced neurodegeneration. We subsequently partitioned candidate causal subnetworks, which were further validated based on human or Drosophila genetic evidence.

Result: Our results highlight hundreds of conserved, differentially expressed genes mapping to AD regulatory networks. Our systematic screening identified 144 tau/Aβ modifiers. We discovered an up-regulated, causal network that is significantly enriched for both AD risk variants and markers of immunity / inflammation, and which promotes Aβ and tau-mediated neurodegeneration based on fly genetic manipulations in neurons. By contrast, a promising synaptic regulatory network is strongly downregulated in human AD and is enriched for loss-of-function suppressors of Aβ/tau, consistent with a potential compensatory response to glutamatergic excitotoxic brain injury.

Conclusion: our cross-species, systems genetic approach establishes a putative causal chain linking AD pathology, large-scale gene expression perturbations, and ultimately, neurodegeneration.