Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Timothy E Richardson; Miranda E Orr; Timothy C Orr; Susan K Rohde; Alexander J Ehrenberg; Emma L Thorn; Thomas D Christie; Victoria Flores-Almazan; Robina Afzal; Claudia De Sanctis; Carolina Maldonado-Díaz; Satomi Hiya; Leyla Canbeldek; Lakshmi Shree Kulumani Mahadevan; Cheyanne Slocum; Jorge Samanamud; Kevin Clare; Nicholas Scibetta; Raquel T Yokoda; Daniel Koenigsberg; Gabriel A Marx; Justin Kauffman; Adam Goldstein; Enna Selmanovic; Eleanor Drummond; Thomas Wisniewski; Charles L White 3rd; Alison M Goate; John F Crary; Kurt Farrell; Michael L Alosco; Jesse Mez; Ann C McKee; Thor D Stein; Kevin F Bieniek; Tiffany F Kautz; Elena V Daoud; Jamie M Walker

doi:10.1002/alz.14487

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Alzheimers Dement. 2024 Dec 31. doi: 10.1002/alz.14487. Online ahead of print.

Authors

Timothy E Richardson¹, Miranda E Orr^{2

3}, Timothy C Orr², Susan K Rohde^{1

4

5

6

7}, Alexander J Ehrenberg^{8

9

10}, Emma L Thorn^{1

11}, Thomas D Christie^{1

11}, Victoria Flores-Almazan^{1

11}, Robina Afzal^{1

11}, Claudia De Sanctis^{1

11}, Carolina Maldonado-Díaz¹, Satomi Hiya¹, Leyla Canbeldek¹, Lakshmi Shree Kulumani Mahadevan¹, Cheyanne Slocum¹, Jorge Samanamud¹, Kevin Clare¹, Nicholas Scibetta¹, Raquel T Yokoda¹², Daniel Koenigsberg^{1

11

13

14

15

16}, Gabriel A Marx^{1

11

13

14

15

16

17}, Justin Kauffman^{1

11

13

14

15

16}, Adam Goldstein^{1

11}, Enna Selmanovic^{13

16}, Eleanor Drummond¹⁸, Thomas Wisniewski^{19

20

21}, Charles L White 3rd²², Alison M Goate^{13

15

23}, John F Crary^{1

11

13

14

15

16}, Kurt Farrell^{1

11

13

14

15

16}, Michael L Alosco^{24

25}, Jesse Mez^{24

25}, Ann C McKee^{24

25

26

27}, Thor D Stein^{24

25

26

27}, Kevin F Bieniek^{28

29}, Tiffany F Kautz²⁹, Elena V Daoud²², Jamie M Walker^{1

11

13

29}

Affiliations

¹ Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
³ St. Louis VA Medical Center, St. Louis, Missouri, USA.
⁴ Department of Pathology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Human Genetics, Genomics of Neurodegenerative Diseases and Aging, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷ Department of Neurology, Alzheimer Center Amsterdam, Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁸ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
⁹ Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
¹⁰ Innovative Genomics Institute, University of California, Berkeley, California, USA.
¹¹ Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
¹³ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Brain & Mind Center and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
¹⁹ Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Department of Psychiatry, New York University Grossman School of Medicine, New York, New York, USA.
²¹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
²² Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
²³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁴ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
²⁵ Boston University Alzheimer's Disease Research Center and BU CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
²⁶ VA Boston Healthcare System, Boston, Massachusetts, USA.
²⁷ VA Bedford Healthcare System, Bedford, Massachusetts, USA.
²⁸ Department of Pathology & Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
²⁹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

PMID: 39737785
DOI: 10.1002/alz.14487

Abstract

Introduction: Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition.

Methods: We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5).

Results: There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders.

Discussion: These results suggest that there are subregion-specific proteomic differences among the neurons of these disorders, which appear to be influenced to a large degree by the presence of hippocampal Aβ. These proteomic differences may play a role in the differing hippocampal p-tau distribution and pathogenesis of these disorders.

Highlights: Alzheimer's disease neuropathologic change (ADNC), possible primary age-related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) can be differentiated based on the proteomic composition of their neurofibrillary tangle (NFT)- and non-NFT-bearing neurons. The proteome of these NFT- and non-NFT-bearing neurons is largely correlated with the presence or absence of amyloid beta (Aβ). Neurons in CTE and definite PART (Aβ-independent pathologies) share numerous proteomic similarities that distinguish them from ADNC and possible PART (Aβ-positive pathologies).

Keywords: Alzheimer's disease neuropathologic change; aging; autophagy; chronic traumatic encephalopathy; cognitive reserve; neurodegeneration; oxidative stress; primary age‐related tauopathy; resilience; resistance; synapse loss; synapses; tauopathy.

Abstract

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