2016 Volume 33 Issue 3 Pages 425-427
Accumulation of amyloid–β peptide (Aβ) in the brain is a triggering event of the long–term pathological cascade of Alzheimer's disease (AD), and is closely associated with the metabolic balance of Aβ. Almost all familial AD mutations of causal genes, such as PSEN1, PSEN2 and APP, cause an increase in the anabolism (production) of a particular form of Aβ, Aβ1–42, leading to Aβ deposition and accelerating progression of AD pathological cascade. As well, a chronic reduction in the Aβ–catabolic (degrading) activity would also promote Aβ deposition. Neprilysin is a rate–limiting peptidase involved in brain Aβ catabolism. Mounting evidence that expression levels of neprilysin are decreased selectively in the hippocampus and cerebral cortex of AD patients from the early stages of disease development and also with aging in humans, suggests a close association of reduced levels of neprilysin with the etiology and pathogenesis of AD. Thus, a subtle but long–term decline in neprilysin activity appears to be at least partly responsible for the memory–related symptoms of AD, and up–regulation of neprilysin would be a promising strategy for disease–modifying therapy of AD.
We screened a compound modulating brain neprilysin activity and/or gene expression using a Nagasaki University natural product library, and found that some polyphenols, such as (–)–epigallocatechin gallate (EGCg) were capable of up–regulating neprilysin. However, the polyphenols are less hydrophobic, and their bioavailabilities and blood–brain barrier permeabilities are not always so good. We developed aliphatic catechin derivatives by introducing an aliphatic moiety into the A–ring of EGCg to increase Log P values. Some of the aliphatic catechin derivatives more strongly up–regulated neprilysin, and another compounds did both neprilysin and α–secretase, which acts to preclude Aβ production, than EGCg did. The aliphatic catechins are expected as promising drug candidates for therapy and prevention of AD.
