Hippocampal mGluR5 levels are comparable in Alzheimer's and control brains, and divergently influenced by amyloid and tau in control brain

Wang, J.; Savodalli, S.; Kong, Y.; Mashio, C.; Konietzko, U.; Klohs, J.; Razansky, D.; Rominger, A.; Mu, L.; Schibli, R.; Hock, C.; Nitsch, R. M.; Ni, R.

doi:10.1101/2024.05.25.595868

bioRxiv · 10.1101/2024.05.25.595868

Hippocampal mGluR5 levels are comparable in Alzheimer's and control brains, and divergently influenced by amyloid and tau in control brain

Wang, J.·Savodalli, S.·Kong, Y.·Mashio, C.·Konietzko, U.·Klohs, J.·Razansky, D.·Rominger, A.·Mu, L.·Schibli, R.·Hock, C.·Nitsch, R. M.·Ni, R.

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Abstract

BackgroundMetabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory formation and in neurodegeneration and amyloid deposition in Alzheimers disease (AD). Conflicting results on the cerebral mGluR5 levels in AD have been reported based on in vivo and postmortem studies. Here, we aimed to assess alterations in hippocampal mGluR5 expression in AD, and the associations between mGluR5 expression and pathologies. MethodsImmunofluorescence staining for mGluR5 was performed on postmortem brain tissue from 34 AD patients and 31 nondemented controls (NCs) and from aged 3xTg and arcA{beta} model mice of AD. Autoradiography was performed on brain tissue slices from arcA{beta} mice using mGluR5 tracer [18F]PSS232. Analysis of different cellular source of GRM5 RNA in human and mouse brains was performed. Proteomic profiling and pathway analysis were performed on hippocampal tissue from aged 3xTg mice and wild-type mice. ResultsNo differences in hippocampal mGluR5 expression or entorhinal cortical GRM5 RNA levels were detected between the AD and NC groups. Hippocampal mGluR5 levels increased with Braak stage and decreased with amyloid level in the NC group. No correlations were detected between the levels of mGluR5 and amyloid, tau, or Iba1/P2X7R in the hippocampus of AD patients and NC cases. Ex vivo autoradiography revealed comparable cerebral levels of [18F]PSS232 in arcA{beta} mice compared to nontransgenic mice. GO and KEGG pathway enrichment analyses revealed that the Shank3, Grm5 and glutamatergic pathways were upregulated in hippocampal tissue from aged 3xTg mice compared to wild-type mice. ConclusionThis study revealed no difference in hippocampal mGluR5 levels between AD patients and NCs and revealed the divergent influence of amyloid and tau pathologies on hippocampal mGluR5 levels in NCs. Species differences were observed in the GRM5 RNA level as well as at the cellular location. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/595868v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@17c69aorg.highwire.dtl.DTLVardef@efbaf9org.highwire.dtl.DTLVardef@dc3c2corg.highwire.dtl.DTLVardef@f27038_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wang, J., Savodalli, S., Kong, Y., Mashio, C., Konietzko, U., Klohs, J., Razansky, D., Rominger, A., Mu, L., Schibli, R., Hock, C., Nitsch, R. M., Ni, R.. 2024-05-26. Hippocampal mGluR5 levels are comparable in Alzheimer's and control brains, and divergently influenced by amyloid and tau in control brain. https://doi.org/10.1101/2024.05.25.595868

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