Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.

Beyond cognitive impairment, Alzheimer's disease (AD) is frequently accompanied by apathy, the most prevalent and burdensome neuropsychiatric symptom (NPS). Apathy significantly impacts AD onset and progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing analysis revealed abnormal immune gene expression uniquely associated with apathy in AD patients. In this study, we investigated whether changes in these immune related genes are also linked to apathy-like behavior, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies apathy-like behaviors in 5xFAD mice. We first validated the apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-18 month-old 5xFAD mice using RT-qPCR. Then separate cohorts of similarly aged 5xFAD mice received SB290157 and/or methylphenidate for three weeks. Our results showed that elevated immune hub genes Tyrobp, C3, C3ar, C1qa, C1qb, and C1qc were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment improved nest-building behavior, reduced C3 and C3ar expression as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.