Trem2 links cardiometabolic inflammation to neurobehavioral dysfunction in HFpEF

Neuroinflammation contributes to neurodegeneration in Alzheimer’s disease (AD), and systemic cardiometabolic inflammation may accelerate these processes through a poorly understood heart–brain axis. Triggering receptor expressed on myeloid cells 2 (Trem2), a microglia-enriched immune receptor and AD risk gene, regulates immune responses to tissue injury and metabolic stress. We previously showed that Trem2 is elevated in cardiac macrophages in a deoxycorticosterone acetate (DOCA)-salt model of heart failure with preserved ejection fraction (HFpEF) and that Trem2 deletion worsens cardiac diastolic function in this model. Here, we tested whether Trem2 deficiency also promotes neurobehavioral dysfunction under cardiometabolic stress. Wild-type (WT) and Trem2 - / - mice underwent uninephrectomy followed by DOCA-salt treatment, while 5xFAD mice (a widely used AD model that carries five familial AD-linked mutations) served as a positive control for Alzheimer’s-like neurodegeneration. Fine motor coordination was assessed using the rotarod test. WT mice exhibited significantly longer rotarod duration compared to 5xFAD mice (p < 0.01). In contrast, Trem2 - / - mice showed significantly impaired performance compared to WT (p < 0.05) and were not significantly different from 5xFAD mice. These data demonstrate that Trem2 is required to preserve fine motor function during cardiometabolic stress and support a Trem2-dependent heart–brain axis linking HFpEF to neurodegenerative dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.