Val 8-glucagon-like peptide-1 protects against Aβ1–40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats

Abstract

Amyloid β protein (Aβ) is considered to be partly responsible for the impairment of learning and memory in Alzheimer disease (AD). In addition, it has been found recently that type 2 diabetes mellitus (T2DM) is a risk factor for developing AD. One promising treatment for AD is using analogues for the insulin-release facilitating gut hormone glucagon-like peptide-1 (GLP-1) that has been developed as a T2DM therapy. GLP-1 has been shown to have neuroprotective properties. However, if GLP-1 can protect the late phase-long term potentiation (L-LTP) and related cognitive function against Aβ-induced impairment it is still an open question. To further characterize the neuroprotective function of GLP-1 in the brain, we investigated the effects of i.c.v. injected Val 8-GLP-1(7–36) on the Aβ fragment-induced impairment of in vivo hippocampal L-LTP and spatial learning and memory in rats. The results showed that (1) Aβ1–40 (5 nmol) injection did not affect the baseline field excitatory postsynaptic potentials (fEPSPs), but significantly suppressed multiple high frequency stimulation (HFS)-induced L-LTP in hippocampal CA1 region; (2) Val 8-GLP-1(7–36) (0.05 pmol) administration alone did not affect the baseline synaptic transmission and the maintenance of L-LTP; (3) pretreatment with Val 8-GLP-1(7–36) (0.05 pmol) effectively prevented Aβ1–40-induced deficit of L-LTP; (4) i.c.v. injection of 5 nmol Aβ1–40 resulted in a significant decline learning a spatial Morris water maze (MWM) test; (5) Val 8-GLP-1(7–36) (0.05 pmol) administration alone did not affect spatial learning in this task, while pretreatment with Val 8-GLP-1(7–36) effectively reversed the impairment of spatial learning and memory induced by Aβ1–40. At the same time, the swim speeds and escape latencies of rats among all groups in the visible platform tests did not show any difference. These results suggest that increase of GLP-1 signalling in the brain may be a promising strategy to ameliorate the degenerative processes observed in AD.