[Towards presymptomatic diagnosis, prevention and treatment of Alzheimer's disease]

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, the pathology of which becomes irreversible as it proceeds downstream of the disease cascade. Therefore, overcoming AD primarily requires early (presymptomatic) diagnosis, followed by preventive treatment. Since accumulation of amyloid beta peptide (A beta) in brain seems to play a central role AD pathogenesis, we established a new imaging technique to visualize A beta plaques in a mouse model of A beta amyloidosis in a non-invasive manner using a high-power MRI. This will open a new avenue to search for biochemical markers that correlate with the pathological parameters. We also found that a dimeric form of A beta, the quantity of which can be metabolically regulated by neprilysin, impairs in vivo neuronal plasticity, i.e. hippocampal long term potentiation. This suggests that reducing A beta dimers by upregulating neprilysin activity is likely to contribute to alleviation of memory-associated symptoms. Finally, we discovered that a neuropeptide, somatostatin, upregulates neuronal neprilysin activity. Because brain somatostatin expression is known to decline during aging, the finding indicates that the aging-induced downregulation of somatostatin may be a trigger for A beta accumulation leading to late-onset sporadic AD development and that somatostatin receptor(s) now emerge as pharmacological target candidates for the prevention and treatment of AD.