TY - JOUR
T1 - Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele
AU - Gal, Jozsef
AU - Katsumata, Yuriko
AU - Zhu, Haining
AU - Srinivasan, Sukanya
AU - Chen, Jing
AU - Johnson, Lance Allen
AU - Wang, Wang Xia
AU - Golden, Lesley Renee
AU - Wilcock, Donna M.
AU - Jicha, Gregory A.
AU - Cykowski, Matthew D.
AU - Nelson, Peter Tobias
N1 - Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - Alleles
KW - Alzheimer Disease/genetics
KW - Amyloid beta-Peptides/metabolism
KW - Apolipoprotein E4/genetics
KW - Apolipoproteins E/metabolism
KW - Biomarkers/metabolism
KW - Dementia/genetics
KW - Detergents
KW - Genotype
KW - Humans
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U2 - 10.1016/j.ajpath.2021.11.013
DO - 10.1016/j.ajpath.2021.11.013
M3 - Article
C2 - 34954207
AN - SCOPUS:85123698486
SN - 0002-9440
VL - 192
SP - 564
EP - 578
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -