biostudies-literatureWalker JMNational Institute of Neurological Disorders and StrokeBLRD VANIA NIH HHSNINDS NIH HHSNational Institute on Aging783-797https://www.ebi.ac.uk/biostudies/studies/S-EPMC10916977biostudies-literatureUnknown20(2)<h4>Introduction</h4>Alzheimer'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.<h4>Methods</h4>Using 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.<h4>Results</h4>Proteomic 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.<h4>Discussion</h4>These 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.<h4>Highlights</h4>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.Alzheimer's & dementia : the journal of the Alzheimer's AssociationSpatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy.PMC10916977R21 AG078505R01 AG065839P30 AG066546U54 AG079754P30 AG066514I01 BX005717R01 AG068293R21 NS125171R24 AG073199T32 AG049688P30 AG066512P01 AG060882K01 AG070326P30 AG044271Orr MEWalker JMMarx GADaoud EVEhrenberg AJOrr TCVij MWhite CLFarrell KChristie TDSelmanovic EWisniewski TYokoda RTKauffman JCrary JFKautz TFThorn ELMcKenzie ATRichardson TEDrummond EfalseSpatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy.<h4>Introduction</h4>Alzheimer'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.<h4>Methods</h4>Using 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.<h4>Results</h4>Proteomic 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.<h4>Discussion</h4>These 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.<h4>Highlights</h4>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.2024-01-01T00:00:00Z2024 Feb2026-06-27T03:18:23.019Z2026-06-27T03:06:20.827ZS-EPMC109169773777784810.1002/alz.13484