Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation

作者：Song M S; Rauw G; Baker G B; Kar S^*

来源：European Journal of Neuroscience, 2008, 28(10): 1989-2002.

DOI：10.1111/j.1460-9568.2008.06498.x

• beta-amyloid-internalization
• Alzheimer's disease
• glutamate
• neurodegeneration
• neuroprotection
• tau phosphorylation

It has been suggested that accumulation of beta-amyloid (A beta) peptide triggers neurodegeneration, at least in part, via glutamate-mediated excitotoxicity in Alzheimer's disease (AD) brain. This is supported by observations that toxicity induced by A beta peptide in cultured neurons and in adult rat brain is known to be mediated by activation of glutamatergic N-methyl-d-aspartate (NMDA) receptors. Additionally, recent clinical studies have shown that memantine, a noncompetitive NMDA receptor antagonist, can significantly improve cognitive functions in some AD patients. However, very little is currently known about the potential role of memantine against A beta-induced toxicity. In the present study, we have shown that A beta(1-42)-induced toxicity in rat primary cortical cultured neurons is accompanied by increased extracellular and decreased intracellular glutamate levels. We subsequently demonstrated that A beta toxicity is induced by increased phosphorylation of tau protein and activation of tau kinases, i.e. glycogen synthase kinase-3 beta and extracellular signal-related kinase 1/2. Additionally, A beta treatment induced cleavage of caspase-3 and decreased phosphorylation of cyclic AMP response element binding protein, which are critical in determining survival of neurons. Memantine treatment significantly protected cultured neurons against A beta-induced toxicity by attenuating tau-phosphorylation and its associated signaling mechanisms. However, this drug did not alter either conformation or internalization of A beta(1-42) and it was unable to attenuate A beta-induced potentiation of extracellular glutamate levels. These results, taken together, provide new insights into the possible neuroprotective action of memantine in AD pathology.

• 出版日期2008-11