Spatial proteomics of hippocampal subfield‐specific pathology in Alzheimer's disease and primary age‐related tauopathy

Abstract

INTRODUCTIONAlzheimer's disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R hyperphosphorylated‐tau (p‐tau)‐positive neurofibrillary tangles (NFTs) but differ in the spatial p‐tau development in the hippocampus.METHODSUsing Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT‐bearing and non‐NFT‐bearing neurons in AD (n = 7) and PART (n = 7) subjects.RESULTSProteomic measures of synaptic health were inversely correlated with the subregional p‐tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aβ) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART.DISCUSSIONThese results suggest subfield‐specific proteome differences that may explain some of the differences in Aβ and p‐tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aβ in the pathologic process.Highlights Synaptic health is inversely correlated with local p‐tau burden. The proteome of NFT‐ and non‐NFT‐bearing neurons is influenced by the presence of Aβ in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.

Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies

“…This is consistent with previous observations that cognitive impairment in PART is correlated more with the overall hippocampal p-tau burden (as opposed to Braak stage), the presence of white matter pathology, and other comorbidities, including LATE-NC and CVD [7,33,44,48,74,90,91,96]. This also supports the idea that definite PART is a separate process from ADNC, and may represent more of a normal aging pattern [16,17,35,90,94,96]. The frequency of ALS/MND was also inversely correlated with global CDR (Table 1), which may be explained by subjects dying of ALS-related complications earlier than subjects without ALS, before more severe cognitive impairment from associated FTLD-TDP could develop.…”

Spatiotemporal multi-omics: exploring molecular landscapes in aging and regenerative medicine

“…Similarly, STM provides a comprehensive view of metabolic changes throughout the aging process. Walker et al [ 197 ] at the University of California produced the first spatial and temporal metabolite map of the mouse brain across the aging spectrum, from adolescence to old age. This extensive dataset, encompassing 1547 molecules across 10 brain regions and 4 developmental stages [ 197 ], highlights significant variations in metabolites with no sex correlation.…”

“…Walker et al [ 197 ] at the University of California produced the first spatial and temporal metabolite map of the mouse brain across the aging spectrum, from adolescence to old age. This extensive dataset, encompassing 1547 molecules across 10 brain regions and 4 developmental stages [ 197 ], highlights significant variations in metabolites with no sex correlation. Notable findings include changes in sphingolipid patterns, indicative of myelin remodeling, and metabolic pathways during aging.…”

Spatial Multiomics Lipids and Gene expression using MALDI ISH MSI

“…8 Technologies, such as MERFISH 9 , RNAScope 10 , and others circumvent this issue, by cycling fluorescent barcodes on and off of mRNA probe constructs, expanding the diversity of genes detected. Similar methodologies enable other spatial transcriptomics-based technologies, such as the Xenium platform 11 , the Geomx digital spatial profiler 12,13 , etc. To date, these systems have been widely used and demonstrate the importance of spatial biology.…”

“…After photolytically cleaving the peptide mass tags from their RNA binding sequences, the tissue is coated in a MALDI matrix and put through a MALDI MSI experiment on a Bruker timsTOF flex. enable other spatial transcriptomics-based technologies, such as the Xenium platform 11 , the Geomx digital spatial profiler 12,13 , etc. To date, these systems have been widely used and demonstrate the importance of spatial biology.…”