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

Jamie M Walker; Miranda E Orr; Timothy C Orr; Emma L Thorn; Thomas D Christie; Raquel T Yokoda; Meenakshi Vij; Alexander J Ehrenberg; Gabriel A Marx; Andrew T McKenzie; Justin Kauffman; Enna Selmanovic; Thomas Wisniewski; Eleanor Drummond; Charles L White 3rd; John F Crary; Kurt Farrell; Tiffany F Kautz; Elena V Daoud; Timothy E Richardson

doi:10.1002/alz.13484

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

Alzheimers Dement. 2024 Feb;20(2):783-797. doi: 10.1002/alz.13484. Epub 2023 Sep 30.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / pathology
Amyloid beta-Peptides / metabolism
Hippocampus / pathology
Humans
Neurofibrillary Tangles / pathology
Proteome
Proteomics
Tauopathies* / pathology
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Proteome
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding