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

Abstract

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.

The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD)

“…We defined S100A8 as a major pathogenic gene of both MCI and AD, which has higher connectivity in MCI and AD PPI networks. An increased expression level of S100A8 aggravated neuronal inflammation by promoting the formation of amyloid β (Aβ) plaques and showed co-localization with Aβ plaques, which was compatible with the activation of astrocytes in the brains of APP23 mice, a mouse model of AD (55). However, our results showed decreased expression of S100A8 in venous blood of patients with MCI or AD, which may be due to the tissue specificity of S100A8 expression level and needs more investigation.…”

S100A6 and Its Brain Ligands in Neurodegenerative Disorders

“…Particularly, the protein was found in pyramidal neurons of the hippocampus and cortex, granule cells in the cerebellum, neurons in the brain stem, in olfactory receptor cells, astrocytes in white matter, some ependymal cells (especially around the central canal), and in Schwann cells. Other studies performed on mouse brain showed high expression of S100A6 in astrocytes localized in the border zones of all brain ventricles, tanycytes of the hypothalamus, and neurons of the olfactory bulb, hippocampus, thalamus, cerebral cortex, brainstem, and cerebellum [18,19]. Interestingly, an increase in S100A6 reactivity in astrocytes of the mouse hippocampus was observed in aged animals [20].…”

“…Exogenous S100A6 was found to reduce the level of protein deposits in APP/PS1 mouse brain sections and to protect cultured COS-7 cells against Zn 2+ toxicity. Another work has shown that in the brain of APP23 mice (AD model), S100A6 was present both in the peripheral and central region of β amyloid plaques [19]. As Zn 2+ co-localizes with senile plaques in AD patients and there is evidence that AD-related cognitive decline depends on the level of extracellular Zn 2+ [35], the ability of S100A6 to bind Zn 2+ may, similarly as in the case of S100B [36], prevent Zn 2+ -induced toxicity.…”

Correlation between Antibodies to Bacterial Lipopolysaccharides and Barrier Proteins in Sera Positive for ASCA and ANCA

“…This elevation of serum level of zonulin and other tight junction proteins indicates that intestinal permeability may be responsible for neurological complications of IBD [23]. At the BBB, S100B and claudin-5 are the most enriched proteins, and their dysfunction has been implicated in neuroinflammatory disorders such as MS, neurodegenerative diseases such as Alzheimer's, and psychiatric disorders including depression and schizophrenia [56,57,106,107].…”