Tau pathology is associated with postsynaptic metabotropic glutamate receptor 5 (mGluR5) in early Alzheimer's disease in a sex-specific manner

Abstract

Introduction: To investigate the associations of metabotropic glutamate receptor 5 (mGluR5) with tau deposition and cognitive ability in patients with early Alzheimer's disease (AD).

Methods: Twenty-six cognitively impaired (CI) and 14 cognitively unimpaired (CU) individuals underwent mGluR5 positron emission tomography (PET) ([¹⁸F]PSS232), amyloid PET ([¹⁸F]florbetapir), and tau PET ([¹⁸F]MK6240), and neuropsychological assessment. The relationships among mGluR5 availability, tau deposition, and neuropsychological assessment were analyzed using Spearman's correlation and mediation analyses.

Results: CI patients had lower mGluR5 in the hippocampus than CU (standardized uptake value ratio [SUVr]: 2.03 ± 0.25 vs 1.79 ± 0.17, p = 0.003). Hippocampal mGluR5 was negatively associated with hippocampal tau deposition (r = -.46, p = 0.003) and positively associated with cognitive performance, but only in women. Hippocampal tau deposition mediated the effect of mGluR5 on cognitive performance.

Discussion: Reduced hippocampal mGluR5 is negatively related with tau deposition in most cortical regions and positively associated with cognitive performance, making it a promising biomarker for AD diagnosis and therapy.

Highlights: Cognitively impaired (CI) patients exhibited lower metabotropic glutamate receptor 5 (mGluR5) availability in the hippocampus than cognitively unimpaired (CU) subjects. Hippocampal mGluR5 availability was negatively associated with tau deposition in widespread cortex. Hippocampal mGluR5 availability was positively associated with cognitive performance. The close association of mGluR5 with tau and cognition performance exists only in females. Tau pathology mediated the relationship between mGluR5 availability and cognition.

Keywords: Alzheimer's disease; metabotropic glutamate receptor 5 (mGluR5); synapse; tau.

FIGURE 1

Distribution of decreased [¹⁸F]PSS232 (A, C) and increased [¹⁸F]MK6240 (B, D) in individuals with CI compared with those with CU according to the VOI and voxelwise analysis (sex, age, and education years were adjusted as covariates). Group comparisons between patients with CI and CU of mean SUVr values in different brain regions were performed with a two‐tailed unpaired t‐test with a significance threshold of p < 0.05. *p < 0.05, **p < 0.01, ***p < 0.001. CI, cognitively impaired; CU, cognitively unimpaired; SUVr, standardized uptake value ratio; VOI, volume of interest.

FIGURE 2

The levels of mGluR5 and Aβ and tau expression in the hippocampus in the AD patients were lower than those of individuals in the CU group. (A–C) The presence of diffuse and dense Aβ plaques (6E10 staining, red) and tau (AT8 staining, purple), with relatively lower fluorescence intensities of mGluR5 (green) in the hippocampus of AD patients compared with those in the CU group. (D–F) Representative 4G8 immunochemical staining for Aβ in hippocampal sections from HCs and AD patients. The nucleus was counterstained with DAPI (white). Scale bars = 2000 µm (A, B) and 50 µm (C). Aβ, amyloid beta; AD, Alzheimer's disease; AVLT‐REC, Auditory Verbal Learning Test delayed recognition scores (24 items); CU, cognitively unimpaired; DAPI, author to provide; HC, author to provide; mGluR5, metabotropic glutamate receptor 5; SUVr, standardized uptake value ratio.

FIGURE 3

The correlation between the hippocampal [¹⁸F]PSS232 and [¹⁸F]MK6240 SUVr in the overall cohort. (A, C–F) Decreased hippocampal mGluR5 availability was associated with increased tau deposition in most of the neocortex. (B) Decreased hippocampal mGluR5 availability was associated with increased hippocampal tau deposition. HIPPO, hippocampus; mGluR5, metabotropic glutamate receptor 5; p _cov, p value with sex, age, education years as a covariate; r _cov, correlation coefficient with sex, age, education years as a covariate; SUVr, standardized uptake value ratio.

FIGURE 4

Correlations of the hippocampal [¹⁸F]MK6240 SUVr and [¹⁸F]PSS232 SUVr with different cognition scores. (A–D) Correlations of hippocampal [¹⁸F]MK6240 with the MMSE, MoCA‐B, AVLT‐LDR, and AVLT‐REC scores. (E–H) Correlations of hippocampal mGluR5 availability with the MMSE, MoCA‐B, AVLT‐LDR, and AVLT‐REC scores. AVLT‐LDR, author to provide; AVLT‐REC, Auditory Verbal Learning Test delayed recognition scores (24 items); mGluR5, metabotropic glutamate receptor 5; MMSE, Mini‐Mental State Examination; MoCA‐B, Montreal Cognitive Assessment‐Basic; SUVr, standardized uptake value ratio.

FIGURE 5

Correlations of the hippocampal [¹⁸F]PSS232 SUVr with [¹⁸F]MK6240 SUVr and different cognitions are only significant in women. A significant interaction of hippocampal mGluR5 was found in correlation with hippocampal tau deposition (A), MMSE (B), and MoCA‐B (C). mGluR5, metabotropic glutamate receptor 5; MMSE, Mini‐Mental State Examination; MoCA‐B, Montreal Cognitive Assessment‐Basic SUVr, standardized uptake value ratio.

FIGURE 6

Analysis of the effects of tau pathology on the associations between hippocampal mGluR5 levels and cognitive decline (MMSE and MoCA‐B scores). (A) Tau pathology mediates the relationships between hippocampal mGluR5 levels and MMSE scores; (B) tau pathology mediates the relationships between hippocampal mGluR5 levels and MoCA‐B scores; sex, age, and education years were adjusted as covariates. mGluR5, metabotropic glutamate receptor 5; MMSE, Mini‐Mental Status Examination; MoCA‐B, Montreal Cognitive Assessment‐Basic.