posted on 2019-07-09, 08:25authored bySimone Hagmeyer, Mariana A. Romão, Joana S. Cristóvão, Antonietta Vilella, Michele Zoli, Cláudio M. Gomes, Andreas M. Grabrucker
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 (Ab) 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 Ab 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 Ab
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 Ab 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
Ab 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.
Funding
Mathematical Sciences: Problems in Singularities of Mappings