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.