In
tauopathies such as
Alzheimer's disease (AD), the moleccular mechanisms of
tau protein agregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration are not fully understood. Recent studies indirectly demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration, especially that induced by the
amyloid (Abeta) pathology.
Lithium is a medication for
bipolar mood disorders. Its therapeutic mechanism of action remains unclear, in part because of the large number of biochemical effects attributed to
lithium. Since
lithium directly inhibits
glycogen synthase kinase-3beta (
GSK3beta), a key
enzyme involved in tau phosphorylation, it was suggested that the
therapeutic use of
lithium could be expanded from
mood disorders to neurodegenerative conditions.
Lithium has been also reported to protect cultured neurons against Abeta toxicity, and to prevent NFTs accumulation and
cognitive impairments in transgenic models of
tauopathies. However, the exact mechanism of neuroprotection provided by
lithium remains unknown. Here, we show that exposure of cultured cortical neurons to
lithium decreased
tau protein levels. This decrease was not linked to the activation of proteolytic processes including calpains,
caspases and
proteasome or to neuronal loss, but was rather associated with a reduction in tau
mRNA levels. Moreover, prior exposure to
lithium, at concentrations effective in reducing
tau protein levels, markedly reduced pre-aggregated Abeta-induced neuronal apoptosis. Our findings raise the possibility that
lithium could exert its
neuroprotective effect against Abeta toxicity through the downregulation of
tau proteins and that, at least, by acting at the level of tau
mRNA.