The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade.
Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aβ. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aβ and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aβ protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aβ, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and Aβ. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aβ aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.
Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden.
Chao
C
Wang
Alexey G
AG
Klechikov
Anna L
AL
Gharibyan
Sebastian K T S
SK
Wärmländer
Jüri
J
Jarvet
Lina
L
Zhao
Xueen
X
Jia
Vinod K
VK
Narayana
S K
SK
Shankar
Anders
A
Olofsson
Thomas
T
Brännström
Yuguang
Y
Mu
Astrid
A
Gräslund
Ludmilla A
LA
Morozova-Roche
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology; D040502:Calgranulin B / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D040502:Calgranulin B; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)