. 2024 Feb;20(2):783-797.

doi: 10.1002/alz.13484. Epub 2023 Sep 30.

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

Jamie M Walker^{1

2

3

4}, Miranda E Orr^{5

6

7}, Timothy C Orr^{5

8}, Emma L Thorn^{1

3}, Thomas D Christie^{1

3}, Raquel T Yokoda¹, Meenakshi Vij¹, Alexander J Ehrenberg^{9

10

11}, Gabriel A Marx^{1

2

3

12

13

14

15}, Andrew T McKenzie^{1

2

3

12

13

15

16}, Justin Kauffman^{1

2

3

12

13

15}, Enna Selmanovic^{2

15}, Thomas Wisniewski^{17

18

19}, Eleanor Drummond²⁰, Charles L White 3rd²¹, John F Crary^{1

2

3

12

13

15}, Kurt Farrell^{1

2

3

12

13

15}, Tiffany F Kautz⁴, Elena V Daoud²¹, Timothy E Richardson^{1

3}

Affiliations

¹ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA.
⁵ Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁶ Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁷ Salisbury VA Medical Center, Salisbury, North Carolina, USA.
⁸ Department of Healthcare Innovations, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁹ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
¹¹ Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, USA.
¹² Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Ronal M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.
¹⁸ Department of Psychiatry, New York University Grossman School of Medicine, New York, New York, USA.
¹⁹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Brain & Mind Center and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
²¹ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

PMID: 37777848
PMCID: PMC10916977
DOI: 10.1002/alz.13484

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

Jamie M Walker et al. Alzheimers Dement. 2024 Feb.

. 2024 Feb;20(2):783-797.

doi: 10.1002/alz.13484. Epub 2023 Sep 30.

Authors

Affiliations

¹ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA.
⁵ Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁶ Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁷ Salisbury VA Medical Center, Salisbury, North Carolina, USA.
⁸ Department of Healthcare Innovations, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁹ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
¹¹ Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, USA.
¹² Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Ronal M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.
¹⁸ Department of Psychiatry, New York University Grossman School of Medicine, New York, New York, USA.
¹⁹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Brain & Mind Center and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
²¹ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

PMID: 37777848
PMCID: PMC10916977
DOI: 10.1002/alz.13484

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.

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.

Keywords: Alzheimer's disease (AD); aging; neurodegeneration; primary age-related tauopathy (PART); resilience; resistance; synapses.

PubMed Disclaimer

Conflict of interest statement

Preliminary results of the data presented in this paper were published in abstract form for the 2023 American Association of Neuropathologists and 2023 Alzheimer's Association International Conference. The authors declare that they have no competing interests, conflicts of interest, or other relevant disclosures. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Representative paired p‐tau (AT8) immunohistochemical stains and immunofluorescent stains demonstrating p‐tau and Aβ pathology in entorhinal cortex, CA1 subregion, and CA2 subregion in a case of Alzheimer's disease (case 1) and primary age‐related tauopathy (case 8). Scale bars in all panels = 200 μm.

**FIGURE 2**
Correlation of presynaptic and postsynaptic proteins with local (subregional) p‐tau burden in all hippocampal subregions. There is a significant inverse relationship between the local p‐tau burden and synaptophysin in both NFT‐bearing neurons and non‐NFT‐bearing neurons (“normal neurons”) and the immediate microenvironments surrounding these neurons (A). This relationship is significant in ADNC cases but not in PART cases (B). Similarly, there is a significant inverse relationship between the local p‐tau burden and neurogranin in both NFT‐bearing neurons and normal neurons and the immediate microenvironments surrounding these neurons (C). This relationship is significant in ADNC cases but only reaches the trend level in PART cases (D).

**FIGURE 3**
Significant differences in protein levels in NFT‐bearing neurons (and their immediate microenvironments) between ADNC and PART in each hippocampal subregion evaluated. ^* p < 0.05; ^** p < 0.01; ^*** p < 0.001.

**FIGURE 4**
Significant differences in protein levels in NFT‐bearing neurons (and their immediate microenvironments) between ADNC, definite PART, and possible PART in each hippocampal subregion evaluated. ^* p < 0.05; ^** p < 0.01; ^*** p < 0.001.

**FIGURE 5**
Significant differences in protein levels in non‐NFT‐bearing neurons (and their immediate microenvironments) between ADNC and PART in each hippocampal subregion evaluated. ^* p < 0.05; ^** p < 0.01; ^*** p < 0.001.

**FIGURE 6**
Significant differences in protein levels in non‐NFT‐bearing neurons (and their immediate microenvironments) between ADNC, definite PART, and possible PART in each hippocampal subregion evaluated. ^* p < 0.05; ^** p < 0.01; ^*** p < 0.001.

**FIGURE 7**
Correlation of protein levels with Thal phase in both NFT‐bearing neurons and non‐NFT‐bearing neurons (“normal neurons”) and the immediate microenvironments surrounding these neurons.

See this image and copyright information in PMC

References

1. Thal DR, Rub U, Orantes M, Braak H. Phases of A beta‐deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791‐1800. - PubMed
1. Braak H, Braak E. Neuropathological stageing of Alzheimer‐related changes. Acta Neuropathol. 1991;82:239‐259. - PubMed
1. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362‐381. - PMC - PubMed
1. Jellinger KA. Different patterns of hippocampal tau pathology in Alzheimer's disease and PART. Acta Neuropathol. 2018;136:811‐813. - PubMed
1. Walker JM, Richardson TE, Farrell K, et al. Early selective vulnerability of the CA2 hippocampal subfield in primary age‐related tauopathy. J Neuropathol Exp Neurol. 2021;80:102‐111. - PMC - PubMed

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

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

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Conflict of interest statement

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