GPR40 receptor activation leads to CREB phosphorylation and improves cognitive performance in an Alzheimer's disease mouse model

Alzheimer's disease (AD) is a very complex neurodegenerative disorder as neuronal loss is a prominent and initial feature of AD. This loss correlates with cognitive deficits more closely than amyloid load. GPR40 receptor belongs to the class of G-protein coupled receptors, is expressed in wide parts of the brain including the hippocampus which is involved in spatial learning and memory. Till now, there are few studies investigating the functional role of GPR40 in brain. In this study, we evaluated the functional role of GPR40 receptor in the A-beta AD mice model. Administration of Aβ1-42 (410 pmol) intracerebroventricularly (i.c.v.) once at the beginning of experiment significantly impaired cognitive performance (in step-through passive test), the ability of spatial learning and memory in (Morris water maze test), working memory, attention, anxiety in (Novel object recognition test), and spatial working and reference-memory in (Hole board discrimination test) compared with the control group. The results revealed that GPR40 receptor treatment groups significantly ameliorated model mice cognitive performance. All GPR40 receptor agonist GW9508, treatment groups enhanced the learning and memory ability in Step-through passive test, Morris water maze test, Hole board discrimination test, Novel object recognition test. Furthermore, we have observed that activation of GPR40 receptor provoked the phosphorylation of the cAMP response element binding protein (CREB) and significant increase in neurotropic factors including brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrohin-4 (NT-4) in mouse hippocampal neurons and contribute to neurogenesis. These results suggest that GPR40 is a suitable therapeutic candidate for neurogenesis and neuroprotection in the treatment and prevention of AD.