Alzheimer's disease risk gene Wwox protects against amyloid pathology through metabolic reprogramming

Genome wide association studies have identified multiple loci that mediate the risk of developing late-onset Alzheimer's Disease (LOAD). The gene WW-domain containing oxidoreductase (WWOX) has been identified in recent LOAD risk meta-analyses, yet its function in the brain is poorly understood. Using Drosophila, we discovered that knockdown of the highly conserved Wwox gene impacts longevity and sleep, having roles in both neuronal and glial subtypes. In an amyloid beta 42 (Aβ42) transgenic model of AD, RNAi- mediated knockdown of Wwox significantly decreased both lifespan and locomotion whilst elevating soluble Aβ42. Transcriptomic and metabolomic analyses revealed that these effects were accompanied by elevated lactate dehydrogenase (Ldh) mRNA and lactate levels, downstream of an increase in the key unfolded protein response protein Atf4. Strikingly, we found that upregulation of Wwox in the Aβ42 model through CRISPR activation significantly reduced amyloid load, improved longevity and locomotion. Multi-omics analysis revealed Wwox upregulation partially reversed several key Aβ42-induced transcriptional pathways in the brain and reduced levels of L-methionine and associated enzymes. These findings support a role for reduced WWOX levels in the genetic risk of developing LOAD via pyruvate metabolism and point towards WWOX activation as a protective therapeutic strategy.