Abstract WP308: TGFBR2 Knockdown Improves Cognitive Function and Breathing in AD Mice

Abstract

Introduction: Respiratory disorders, including sleep apnea, are an independent risk factor for the development of cognitive dysfunction and dementia. Disordered breathing occurs frequently in patients with AD (Alzheimer’s Disease). Disruption of the brainstem breathing centers, including the Retro-trapezoid nucleus (RTN), leads to breathing disorders. Our previous work showed that upregulation of Transforming Growth Factor Beta Receptor 2 (TGFBR2) signaling in the RTN leads to respiratory dysfunction in mice. The present study investigated if inhibiting TGFBR2 selectively in the RTN region could improve breathing and cognitive function in AD mice. Methods: We used 20 WT and 20 TG2576 mice (15 months old). Mice were randomly assigned into two sub-groups; treatment with a shTGFBR2 vector (knockdown) or vector control with scrambled shRNA. After baseline behavior and breathing testing, lentiviral stereotaxic injections of vehicle and shTGFBR2 were done directly into the RTN. After 6 weeks, behavior and breathing testing was performed, and then brain tissues were collected for histological analysis. All the data are presented as Mean±SEM. Results: Tg2576 mice had significantly higher number of apnea (7.91±0.95) than WT mice (4.10±0.85) with a p -value of 0.0079. When injected with shTGFBR2 into the RTN, Tg2576 had improved recognition of a novel object (69.24%±5.75) as compared to the Tg2576 vehicle-treated group (51.02%±4.88) in the NORT ( p =0.0213). They also showed a significant improvement in the latency to escape (64.94±15.56) compared to the Tg2576 vehicle-treated group (136.4±20.90) in the Barnes maze ( p =0.0109). The number of apneas was also significantly reduced in TG2675 mice treated with shTGFBR2 in the RTN (3.33±0.69), when compared to the Tg2576 vehicle-treated group (8.22±1.30) with a p -value of 0.0029. Conclusions: Our study revealed that the knockdown of TGFBR2 in the RTN, a brainstem nucleus involved in respiratory control, improved both the cognitive and breathing phenotypes in AD-model mice. Our work suggests that improving respiratory control and reducing apnea in AD may be a potential treatment for the disease. This is especially relevant as new treatments for central apnea, such as phrenic nerve stimulation, are available.