TY - JOUR
T1 - Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status
AU - Kloske, Courtney M.
AU - Dugan, Adam J.
AU - Weekman, Erica M.
AU - Winder, Zachary
AU - Patel, Ela
AU - Nelson, Peter T.
AU - Fardo, David W.
AU - Wilcock, Donna M.
N1 - Publisher Copyright:
© 2021 Oxford University Press. All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-e4 significantly increases AD risk, APOE-e3 is the most common gene variant, and APOE-e2 protects against AD. However, the underlying mechanisms of APOE-e4 on AD risk remains unclear, with APOEe4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-e3/3 (n 9) or APOE-e4/4 (n 10) participants with AD pathology and APOE-e3/3 (n 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-e4/4-AD individuals compared to APOE-e3/3- AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-e3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-e4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.
AB - Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-e4 significantly increases AD risk, APOE-e3 is the most common gene variant, and APOE-e2 protects against AD. However, the underlying mechanisms of APOE-e4 on AD risk remains unclear, with APOEe4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-e3/3 (n 9) or APOE-e4/4 (n 10) participants with AD pathology and APOE-e3/3 (n 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-e4/4-AD individuals compared to APOE-e3/3- AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-e3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-e4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.
KW - Alzheimer disease
KW - Apolipoprotein E
KW - Microglia
KW - NanoString
KW - Neuroinflammation
KW - Neuropathology
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UR - http://www.scopus.com/inward/citedby.url?scp=85123226566&partnerID=8YFLogxK
U2 - 10.1093/jnen/nlab085
DO - 10.1093/jnen/nlab085
M3 - Article
C2 - 34486652
AN - SCOPUS:85123226566
SN - 0022-3069
VL - 80
SP - 922
EP - 932
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 10
ER -
