Dataset Information

β1-adrenergic receptor activation enhances memory in Alzheimer's disease model.

ABSTRACT:

Objective

Deficits in social recognition and learning of social cues are major symptoms of neurodegenerative disorders such as Alzheimer's disease (AD). Here we studied the role of β₁-noradrenergic signaling in cognitive function to determine whether it could be used as a potential therapeutic target for AD.

Methods

Using pharmacological, biochemical and behavioral tools, we assessed social recognition and the β₁-adrenergic receptor (ADR) and its downstream PKA/phospho-CREB (pCREB) signaling cascade in the medial amygdala (MeA) in Thy1-hAPP^Lond/Swe+(APP) mouse model of AD.

Results

Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the β₁-adrenergic system. Moreover, betaxolol, a selective β₁-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of β₁-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective β₁-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB.

Interpretation

Our data indicate that activation of β₁-ADR in MeA is essential for learning of social cues, and that an impairment of this cascade in AD may contribute to pathogenesis and cognitive deficits. Therefore, selective activation of β₁-ADR may be used as a therapeutic approach to rescue memory deficits in AD. Further safety and translational studies will be needed to ensure the safety of this approach.

SUBMITTER: Coutellier L

PROVIDER: S-EPMC4036739 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:CD8+ T cells are essential components of the body’s immune reaction against viral infections and tumors, capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion. Exhausted CD8+ T cells are characterized by expression of multiple inhibitory receptors, like PD-1 and TIM3 and reduced capacity to secrete cytokines, and are commonly found in chronic viral infections, like HIV and HBV, as well as in immunosuppressive tumor microenvironments (TME). Cancer and chronic infection also place considerable stress on tissue architecture and function, and while it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a previously undescribed link between the stress-associated catecholamines adrenaline and noradrenaline and the development of T cell exhaustion through the β1-adrenergic receptor, ADRB1. We identify that exhausted CD8+ T cells express higher levels of ADRB1, and exposure of ADRB1-expressing T cells to catecholamines suppresses cytokine production and impairs T cell proliferation. Genetic or pharmacological ablation of β-adrenergic signaling via ADRB1 reduces development of T cell exhaustion in a chronic infection model and improves cytotoxic functions in tumor-infiltrating lymphocytes (TILs) when combined with immune checkpoint blockade (ICB) therapy in a melanoma model. Extending these findings to an ICB-resistant tumor model of murine pancreatic cancer, we show that beta-blockers and ICB synergize to enhance and reprogram T cell responses. Given that malignant disease is associated with increased systemic catecholamine levels in patients and therapeutic stress reduction improves survival in cancer patients, our results demonstrate a potential link between systemic stress, tumor innervation and immune responses. Our findings show that β-adrenergic signaling constitutes a novel targetable immune checkpoint in CD8+ T cells to rejuvenate antitumor functions. More broadly, our results support further clinical investigation into the application of beta-blockers, which are clinically safe and widely prescribed, as an immunomodulating agent for cancer immunotherapy.