The pathological hallmarks of Alzheimer’s disease derive from compensatory responses to NMDA receptor insufficiency

Abstract

Alzheimers disease is characterized by intracellular aggregates of hyperphosphorylated tau protein and extracellular plaques of amyloid {beta} peptide, a product of APP processing. The origin of these pathological hallmarks has remained elusive. Here, we have tested the idea that both alterations, at the onset of the disease, may constitute compensatory responses to the same causative and initial trigger, namely NMDA receptor insufficiency. Treatment of rat cortical neurons with the specific NMDA receptor antagonist AP5 within 4 h caused a significant increase in tau phosphorylation at the AT8 and S404 epitopes as well as an increase in APP expression and A{beta} 40 secretion. Single intraperitoneal injections of the NMDA receptor open channel blocker MK-801 into wild-type mice reproduced all of these changes in a brain region-specific fashion either at latency 4 h or 24 h. Subchronic treatment with MK-801 for 6 weeks induced AT8, S404 and S396 immunoreactivity selectively in female mice. We conclude that the pivotal pathological alterations in Alzheimers disease represent runaway physiological responses to persistently insufficient excitatory neurotransmission. In view of the evidence for excitatory insufficiency in trisomy 21 patients, PS1 mutation carriers and ApoE4 carriers, our data suggest a common pathomechanism behind familial, sporadic, and risk allele-triggered Alzheimers disease. The potential of this mechanism to reconcile previous conflicting observations is discussed.