Declines of hippocampal metabotropic glutamate receptor in Alzheimer's disease

Glutamatergic networks subserve the vast majority of motor, sensory and integrative brain functions. In these networks, metabotropic glutamate receptor type five (mGLUR5) modulates plastic changes associated with efficiency of glutamate neurotransmission. Pre-clinical studies strongly suggest that mGLUR5 plays a role in Alzheimer's disease. Human hippocampi tissue were obtained from from AD patients (N = 5, age 72 ± 4.39) and healthy controls (N = 5, age 69.67 ± 5.61) (Brain Bank of Douglas Hospital, Montreal, Canada). The tissue was cryosectioned (20 μm thick) and a saturation binding study was carried out. The slides were pre-incubated for 20 min in buffer containing 30 mM Na HEPES, 110 nM NaCl, 5 mM KCl, 2.5 mM CaCl2 and 1.2 mM MgCl2 (pH 7.4) and then incubated for 60 min in the presence of [3H]ABP688 (74 Ci/mmol) at a range of concentrations from 0.125 to 8 nM. Non-specific binding was determined with addition of 10 μM of the mGLUR5 antagonist MPEP in adjacent sections. After the incubation, the slides were washed (3 x 5 min) in cold buffer, dipped in ice-cold distilled water and dried. The sections along with autoradiographic standards were exposed for five days to phosphor imaging plates. The Bmax and KD of [3H]ABP688 from both groups were calculated by saturation binding analysis and compared using F-test (p < 0.05). Saturation binding using [3H]ABP688 revealed higher Bmax in the control group (Ctrl, 1.31 ± 0.06; AD 0.711 ± 0.03 pmol/mg of tissue). Binding of [3H]ABP688 in human hippocampal cryosections was blocked after addition of 10 μM MPEP (Figure 1). The nearly 50% reduction in total concentration of receptors in the AD hippocampi was statistically significant (p < 0.001). The KD (1.43 ± 0.2 nM) did not change across groups. Our results indicate mGLUR5 vulnerability in AD. These results support the use of mGLUR5 PET molecular agents for imaging glutamatergic abnormalities in AD patients.