Plexin-A4 mediates amyloid-β-induced tau pathology in Alzheimer's disease animal model

Amyloid-beta (A beta) and tau are major pathological hallmarks of Alzheimer's disease (AD). Several studies have revealed that A beta accelerates pathological tau transition and spreading during the disease progression, and that reducing tau can mitigate pathological features of AD. However, molecular links between A beta and tau pathologies remain elusive. Here, we suggest a novel role for the plexin-A4 as an A beta receptor that induces aggregated tau pathology. Plexin-A4, previously known as proteins involved in regulating axon guidance and synaptic plasticity, can bound to A beta with co-receptor, neuropilin-2. Genetic downregulation of plexin-A4 in neurons was sufficient to prevent A beta-induced activation of CDK5 and reduce tau hyperphosphorylation and aggregation, even in the presence of A beta. In an AD mouse model that manifests both A beta and tau pathologies, genetic downregulation of plexin-A4 in the hippocampus reduced tau pathology and ameliorated spatial memory impairment. Collectively, these results indicate that the plexin-A4 is capable of mediating A beta-induced tau pathology in AD pathogenesis.