S100 Proteins in Alzheimer's Disease

Abstract

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.

Keywords: amyloid-β; metal ions; neuroinflammation and neurodegeneration; protein misfolding and aggregation; tau.

FIGURE 1

S100 proteins are involved in the main processes associated with Alzheimer’s disease (AD). In the AD brain, affected neurons (central panel) are damaged due to the formation of intracellular neurofibrillary tangles (represented by the blue dot) and extracellular amyloid species including an ensemble of low molecular weight aggregates, protofibrils and fibrils (represented by the red dot). As a result of astrocyte and microglia over-activation, some S100 proteins become upregulated, being implicated in several molecular processes altered in AD (A–D). (A) Tau phosphorylation and NFT formation. S100A1, S100A6 and S100B are involved in the disassembly of microtubules and Tau release, while S100A9 and S100B are found within neurofibrillary tangles. (B) APP processing. Several S100 proteins are implicated in APP cleavage and its amyloidogenic processing. S100A9 regulates γ- and β-secretase expression and activity and S100B and S100A1 regulate APP levels. Moreover, S100A7, S100A8, S100A9 and S100B influence Aβ levels (Table 1). (C) Zinc homeostasis. Due to their zinc-binding properties, S100B and S100A6 have zinc-buffering activities that are related to neuroprotective roles; and S100A6 reduces zinc levels and senile plaque load in PS/APP mouse brains. (D) Amyloid β aggregation. S100A1, S100A9, and S100B proteins can interact, modulate the aggregation and co-aggregate with the Aβ peptide. Several S100 proteins (S100B, S100A1, S100A6, S100A8, S100A9, and S100A12), are found within amyloid plaques and in astrocytes and/or microglia around amyloid deposits. Further details and references can be found in the text and in Table 1.