Aβ metabolic mechanism

Nobuhisa Iwata

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute

Accumulation of Aβ, which is produced by a physiological metabolism of amyloid precursor protein, in the brain is a triggering event leading to the pathological cascade of AD. Neprilysin is the presynaptic Aβ-degrading enzyme capable of degrading both oligomeric and monomeric forms of Aβ. A reduction in neprilysin activity in the mouse brains elevates Aβ oligomers, which are highly toxic forms of Aβ aggregates, at the synapses, and leads to impaired hippocampal synaptic plasticity and cognitive functions. Clinical evidence that levels of both neprilysin and somatostatin are falling down in the hippocampus and cerebral cortex from early stages of AD development suggests a close association of neprilysin with the etiology and pathogenesis of AD. Thus, a decline in neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of AD. However, we have already identified somatostatin, which is one of neuropeptides and acts via G-protein-coupled receptors, as a modulator that enhances neuronal neprilysin activity, resulting in a decrease of Aβ levels. Therefore, enhancing neprilysin activity represents an effectual and promising strategy for the therapy and prevention.

Address correspondence to Dr. Nobuhisa Iwata, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute (2-1 Hirosawa, Wako, Saitama 351-0198, Japan)