Proteome imaging using maldi in an alzheimer’s disease mouse model: differential expression of memory-related hippocampal proteins in female and male mice

One of the neuropathological hallmarks of early Alzheimer’s disease (AD) is hippocampal dysfunction caused by amyloid-β (Aβ) accumulation. Previously, our group showed a shifting in the LTP/LTD threshold leading to memory deficits in a murine model of early Aβ amyloidosis in male and female mice. Some protein changes underlying those deficits in the hippocampus have been previously studied, but how proteins might change in each hippocampal subfield has not been investigated. Since each subfield has its own function, we postulated that there could be protein changes that are unique to each, which might also be sex-dependent. To do so, an innovative proteomics study was performed to assess the whole hippocampal proteome using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry that allows protein detection with spatial resolution directly in tissue sections. 24 brains from C57BL/6 adult male and female mice intracerebroventricularly injected with Aβ1-42 or vehicle were used. MALDI imaging was performed using RapifleXTM MALDI TissuetyperTM TOF/TOF mass spectrometer followed by protein identification by traditional MS/MS directly on the tissue. To precisely delineate each anatomical hippocampal subfield, a Nissl staining was performed at the succeeding tissue sections. Of the 235 peptides detected, significant differences in expression levels were found in 34 proteins, due to treatment, sex, or hippocampal location. The present work focuses on 15 of these proteins previously related to AD. Moreover, a significant protein-protein interaction (PPI) was observed, showing a relationship to long-term potentiation (LTP), the functional basis of memory processes. The specific hippocampal subfields’ changes in the proteome caused by early amyloidosis provide new insight in the pathogenesis of AD and valuable potential biomarkers for early diagnosis. Acknowledgements: Grants PID2020-115823-GB100/ MCIN/AEI/10.13039/501100011033 and SBPLY/21/180501/000150/ JCCM and “ERDF A way of making Europe” both to LJ-D and JDN-L. Margarita Salas Postdoctoral Research Fellow to AC funded by European Union NextGenerationEU/PRTR. Declaration of Interest Statement: None