The Environmental Toxin Arsenite Induces Tau Hyperphosphorylation

Abstract

Abnormally hyperphosphorylated tau polymers known as paired helical filaments constitute one of the major characteristic lesions that lead to the demise of neurons in Alzheimer's disease. Here, we demonstrate that the environmental toxin arsenite causes a significant increase in the phosphorylation of several amino acid residues (Thr-181, Ser-202, Thr-205, Thr-231, Ser-262, Ser-356, Ser-396, and Ser-404) in tau, which are also hyperphosphorylated under pathological conditions. Complementary phosphopeptide mapping revealed a dramatic increase in the (32)P-labeling of many peptides in tau following arsenite treatment. Although arsenite activates extracellular-signal regulated kinases-1/-2 and stress-activated protein kinases, these enzymes did not contribute to the arsenite-increased phosphorylation, nor did they appear to normally modify tau in vivo. Tau phosphorylation induced by arsenite did not involve glycogen synthase kinase-3 or protein phosphatase-1 or -2, but the activity responsible for tau hyperphosphorylation could be inhibited with the protein kinase inhibitor roscovitine. The effects of arsenite on the phosphorylation of some tau mutations (DeltaKappa280, V337M, and R406W) associated with frontal-temporal dementia with parkinsonism linked to chromosome 17 was analyzed. The unchallenged and arsenite-induced phosphorylation of some mutant proteins, especially R406W, was altered at several phosphorylation sites, indicating that these mutations can significantly affect the structure of tau in vivo. Although the major kinase(s) involved in aberrant tau phosphorylation remains elusive, these results indicate that environmental factors, such as arsenite, may be involved in the cascade leading to deregulation of tau function associated with neurodegeneration.

Mutually Exclusive Subsets of BH3-Only Proteins Are Activated by the p53 and c-Jun N-Terminal Kinase/c-Jun Signaling Pathways during Cortical Neuron Apoptosis Induced by Arsenite

“…However, inhibition of these pathways did not result in complete protection from apoptosis. Arsenite has also been shown to cause hyperphosphorylation of tau (33) and to upregulate genes associated with endoplasmic reticulum (ER) stress (68) in cortical neuron cultures, but the signals mediating these responses are not known. In other cell types arsenite is also a potent inducer of the p53 pathway (28,85,113), and it can also inhibit survival pathways that play a role in the CNS, such as that mediated by NF-B (8), by oxidation of a critical cysteine in IB kinase (49).…”

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

“…ii) increased APP expression and B amyloid formation [34], iii) impaired synaptic transmission [35], increased tau protein phosphorylation [36,37], and reticulum endoplasmic stress induction [38].…”

Alzheimer's Disease with Markedly Elevated Arsenic and Other Metals Masquerading as Organic Brain Syndrome and Affective Disorder

“…Long-term exposure to As was associated with poor memory and executive function in [8,9,14]. Several studies suggest high cerebral levels of arsenic may contribute to cognitive dysfunction [15]. As also increases Tau phosphorylation and increases transcription of the amyloid protein precursor gene [15,16].…”

“…Several studies suggest high cerebral levels of arsenic may contribute to cognitive dysfunction [15]. As also increases Tau phosphorylation and increases transcription of the amyloid protein precursor gene [15,16]. In addition, As alters amyloid precursor protein metabolism or catabolism increasing both APP and sAPPbeta levels and ABeta [1,17].…”