Calprotectin influences the aggregation of metal-free and metal-bound amyloid-β by direct interaction

Lee, Hyuck Jin; Savelieff, Masha G.; Kang, Juhye; Brophy, Megan Brunjes; Nakashige, Toshiki G.; Lee, Shin Jung C.; Nolan, Elizabeth M.; Lim, Mi Hee

doi:10.1039/c8mt00091c

Cited by 10 publications

(5 citation statements)

References 87 publications

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“…For S100B this effect has been shown to result from a direct physical interaction with Aβ42 (Cristóvão et al, 2018) and at this stage we can only speculate that similar phenomena might also be occurring for S100A6 and S100A8. In support of this possibility is the evidence that the S100A8-containing heterodimer calprotectin interacts with Aβ40, also influencing its aggregation (Lee et al, 2018).…”

Section: Resultsmentioning

confidence: 97%

Distribution and Relative Abundance of S100 Proteins in the Brain of the APP23 Alzheimer’s Disease Model Mice

et al. 2019

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Increasing evidence links proteins of the S100 family to the pathogenesis of Alzheimer’s disease (AD). S100 proteins are EF-hand calcium-binding proteins with intra- and extracellular functions related to regulation of proliferation, differentiation, apoptosis, and trace metal homeostasis, and are important modulators of inflammatory responses. For example, S100A6, S100A8, and S100B expression levels were found increased in inflammatory diseases, but also neurodegenerative disorders, and S100A8/A9 complexes may provide a mechanistic link between amyloid-beta (Aβ) plaque formation and neuroinflammation. On the other hand, S100B, a proinflammatory protein that is chronically up-regulated in AD and whose elevation precedes plaque formation, was recently shown to suppress Aβ aggregation. Here, we report expression of S100A6 and S100B in astrocytes and less so in neurons, and low level of expression of S100A8 in both neurons and glial cells in vitro . In vivo , S100A8 expression is almost absent in the brain of aged wildtype mice, while S100A6 and S100B are expressed in all brain regions and most prominently in the cortex and cerebellum. S100B seems to be enriched in Purkinje cells of the cerebellum. In contrast, in the brain of APP23 mice, a mouse model for Alzheimer’s disease, S100B, S100A6, and S100A8 show co-localization with Aβ plaques, compatible with astrocyte activation, and the expression level of S100A8 is increased in neural cells. While S100A6 and S100B are enriched in the periphery of plaques where less fibrillar Aβ is found, S100A8 is more intense within the center of the inclusion. In vitro assays show that, similarly to S100B, S100A6, and S100A8 also delay Aβ aggregation suggesting a regulatory action over protein aggregation. We posit that elevated expression levels and overlapping spatial distribution of brain S100 proteins and plaques translates functional relationships between these inflammatory mediators and AD pathophysiology processes that uncover important molecular mechanisms linking the aggregation and neuroinflammation cascades.

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Section: Resultsmentioning

confidence: 97%

Distribution and Relative Abundance of S100 Proteins in the Brain of the APP23 Alzheimer’s Disease Model Mice

et al. 2019

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“…We observed a discrete and novel set of differentially expressed genes that discriminated recovery-phase microglia both from control and from early or late disease. A key feature was upregulation of the calcium-binding heterodimer calprotectin ( S100a8 and S100a9 ), a marker of microglial activity that is elevated in schizophrenia [ 48 ], multiple sclerosis [ 49 ] and Alzheimer’s disease [ 50 ], where it may contribute to amyloidogenesis [ 51 ] and activate TLR4 signalling [ 52 ]. The additional calcium sensors S100a6 and S100a11 were also upregulated during recovery.…”

Section: Discussionmentioning

confidence: 99%

Microglial transcriptome analysis in the rNLS8 mouse model of TDP-43 proteinopathy reveals discrete expression profiles associated with neurodegenerative progression and recovery

Hunter

Spiller

Dominique

et al. 2021

acta neuropathol commun

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The microglial reaction is a hallmark of neurodegenerative conditions, and elements thereof may exert differential effects on disease progression, either worsening or ameliorating severity. In amyotrophic lateral sclerosis (ALS), a syndrome characterized by cytoplasmic aggregation of TDP-43 protein and atrophy of motor neurons in the cortex and spinal cord, the transcriptomic signatures of microglia during disease progression are incompletely understood. Here, we performed longitudinal RNAseq analysis of cortical and spinal cord microglia from rNLS8 mice, in which doxycycline-regulatable expression of human TDP-43 (hTDP-43) in the cytoplasm of neurons recapitulates many features of ALS. Transgene suppression in rNLS8 mice leads to functional, anatomical and electrophysiological resolution that is dependent on a microglial reaction that is concurrent with recovery rather than disease onset. We identified basal differences between the gene expression profiles of microglia dependent on localization in spinal cord or cortex. Microglia subjected to chronic hTDP-43 overexpression demonstrated transcriptomic changes in both locations. We noted strong upregulation of Apoe, Axl, Cd63, Clec7a, Csf1, Cst7, Igf1, Itgax, Lgals3, Lilrb4, Lpl and Spp1 during late disease and recovery. Importantly, we identified a distinct suite of differentially expressed genes associated with each phase of disease progression and recovery. Differentially expressed genes were associated with chemotaxis, phagocytosis, inflammation, and production of neuroprotective factors. These data provide new insights into the microglial reaction in TDP-43 proteinopathy. Genes differentially expressed during progression and recovery may provide insight into a unique instance in which the microglial reaction promotes functional recovery after neuronal insult.

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“…In PS/APP mice, the S100A8/A9 heterodimer is found to be upregulated in microglial cells surrounding amyloid plaques (Kummer et al, 2012). Additionally, it is reported that S100A8/A9 binds directly to Aβ40 and that it interferes with amyloid formation but no effect was observed over Aβ42 aggregation (Lee et al, 2018). There is also a link between S100A8/A9 and the “non-amyloidogenic” α-secretase ADAM-10, since S100A8/A9 has lower expression in AD mice models overexpressing ADAM-10 (Prinzen et al, 2009).…”

Section: The S100 Protein Familymentioning

confidence: 99%

S100 Proteins in Alzheimer’s Disease

2019

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S100 proteins are calcium-binding proteins that regulate several processes associated with Alzheimer’s disease (AD) but whose contribution and direct involvement in disease pathophysiology remains to be fully established. Due to neuroinflammation in AD patients, the levels of several S100 proteins are increased in the brain and some S100s play roles related to the processing of the amyloid precursor protein, regulation of amyloid beta peptide (Aβ) levels and Tau phosphorylation. S100 proteins are found associated with protein inclusions, either within plaques or as isolated S100-positive puncta, which suggests an active role in the formation of amyloid aggregates. Indeed, interactions between S100 proteins and aggregating Aβ indicate regulatory roles over the aggregation process, which may either delay or aggravate aggregation, depending on disease stage and relative S100 and Aβ levels. Additionally, S100s are also known to influence AD-related signaling pathways and levels of other cytokines. Recent evidence also suggests that metal-ligation by S100 proteins influences trace metal homeostasis in the brain, particularly of zinc, which is also a major deregulated process in AD. Altogether, this evidence strongly suggests a role of S100 proteins as key players in several AD-linked physiopathological processes, which we discuss in this review.

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Calprotectin influences the aggregation of metal-free and metal-bound amyloid-β by direct interaction

Cited by 10 publications

References 87 publications

Distribution and Relative Abundance of S100 Proteins in the Brain of the APP23 Alzheimer’s Disease Model Mice

Distribution and Relative Abundance of S100 Proteins in the Brain of the APP23 Alzheimer’s Disease Model Mice

Microglial transcriptome analysis in the rNLS8 mouse model of TDP-43 proteinopathy reveals discrete expression profiles associated with neurodegenerative progression and recovery

S100 Proteins in Alzheimer’s Disease

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