Abstract Body: Dementia is associated with respiratory dysfunction. In mice models of dementia, there is increased astrogliosis in the brain stem retro-trapezoid nucleus (RTN), which is crucial for breathing control. Our previous work using a genetic approach suggested that increased transforming growth factor beta receptor (TGFβR) signaling may be responsible for RTN astrogliosis and contribute to respiratory and cognitive dysfunctions. Here we tested our hypothesis that pharmacological inhibition of TGFβR2 in mice models of dementia may reduce RTN gliosis, breathing disorder and cognitive impairment.
We used male 16-month-old Tg-2576 and Tg-SwDI mice that model Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively with WT controls. LY2109761, a selective TGF-β receptor inhibitor, was administered orally every day for 6 weeks at a 50 mg/kg dose. Barnes Maze and Novel Object Recognition Test (NORT) were used to measure cognitive strength, and plethysmography was used to measure respiratory metrics such as apnea rate after the 6 weeks of treatment. Immunofluorescence was used to quantify gliosis (GFAP) at RTN. All data is presented as Mean±SEM.
Tg-2576 mice performed significantly worse than the WTs in the Barnes Maze (escape latency 184±20.99 vs. 119.4±12, p=.039, n=8-9/group), in the NORT (percentage time with the novel object 48.3±2.061 vs. 63.3±2.071, p=.0003, n=8-9/group), and showed increased apneas per minute (9±.9 vs 4.33±.81, p=.001, n=8-9/group). Similarly, Tg-SwDI mice showed impaired breathing and cognition function. In Tg-2576 mice, TGFβR2 inhibition improved performances in Barnes Maze (112±18.6 vs. 184±20.9, p= .02 n=8-9/group) and NORT (57.7±2.54 vs. 48.3±2.06, p=.023, n=8-9/group), and reduced apneas per minute (4.88±.058 vs. 9.0±.98, p=.004, n=8-9/group) compared with vehicle treatment. In Tg-SwDI mice, TGFβR2 inhibition also improved performance in Barnes Maze (43.8±2.72 vs. 58.2±5.16, p=.03 n=7/group) and NORT (59.1±3.28 vs. 46.6±3.32, p=.02, n=7/group), and reduced apneas per minute (5±1.06 vs. 9.71±1.71, p=.038 n=7/group) compared with vehicle group. TGFβR2 pharmacological inhibition additionally reduced astrogliosis in the RTN of Tg-2576 mice (drug 53.62±4.8 vs. vehicle 70.9±3.38, p=.018, n= 4/group).
In conclusion, pharmacological inhibition of TGFβR2 improved cognition in AD and CAA mice. Improving breathing control via reducing gliosis at breathing center RTN may be the underlying mechanisms of the improvement.