Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele

Jozsef Gal, Yuriko Katsumata, Haining Zhu, Sukanya Srinivasan, Jing Chen, Lance Allen Johnson, Wang Xia Wang, Lesley Renee Golden, Donna M. Wilcock, Gregory A. Jicha, Matthew D. Cykowski, Peter Tobias Nelson

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The amygdala is vulnerable to multiple or “mixed” mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementia-associated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer's Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/Aβ, and α-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE ε4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE ε3/ε3 subjects’ amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an “upstream” genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE ε4 allele.

Original languageEnglish
Pages (from-to)564-578
Number of pages15
JournalAmerican Journal of Pathology
Issue number3
StatePublished - Mar 2022

Bibliographical note

Funding Information:
Supported by NIH grants P30 AG072946 (P.T.N. and Dr. Linda Van Eldik), R01 AG042419 (P.T.N.), R01 AG042475 (P.T.N.), R01 AG061111 (P.T.N.), R01 AG057187 (P.T.N.), R21 AG061551 (P.T.N.), RF1 NS118584 (M.D.C.), R01 AG060056 (L.A.J.), R01 AG062550 (L.A.J.), and R21 NS095299 (J.G.); and the VA MERIT award I01 BX002149 (H.Z.). The Orbitrap mass spectrometer was acquired by NIH Grant S10 RR029127 (H.Z.).

Publisher Copyright:
© 2022 American Society for Investigative Pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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