A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice

•AEP-TrkB axis is upregulated in chronic stress-induced depressive-like behaviors.•TrkB cleavage by AEP links neuroinflammation and impaired neurotrophic signaling, mitochondrial dysfunction in depression.•AEP cleaves TrkB and disrupts BDNF/TrkB-mediated AMPARs membrane insertion.•TrkB 1–486 produced by AEP-mediated cleavage binds and suppresses PPAR-δ, leading to mitochondrial dysfunction. Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1β-C/EBPβ-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1–486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1–486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1–486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer’s disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.