Alzheimer' s disease: Is a dysfunctional mevalonate biosynthetic pathway the master-inducer of deleterious changes in cell physiology?

Abstract

There is a growing awareness that the proteins—amyloid-beta (Aβ) and tau—do not cause Alzheimer' s disease (AD) but are produced as a result of it. Similarly, doubt reigns over the degree of causality of high plasma cholesterol and prenylation in AD. This review proposes a fresh and important perspective, in addition to the current line of thinking. It emerges from comparative analysis, in evolutionary retrospect, of the characteristics of the mevalonate biosynthetic pathways in insects versus vertebrates, and of the drastic effects of the absence of farnesol and its esters with juvenile hormone (JH) activity. A dysfunctional mevalonate biosynthetic pathway, with farnesol at its very heart, can disturb “Golgicrine” activity, reduce mitochondrial multiplication, alter Ca2+ homeostasis, and cause massive apoptosis in specific tissues. These effects were observed in insects in the 1960-70s. It became undeniably established that the absence of endogenous sesquiterpenoids farnesol and its JH esters is the direct inducer of complete metamorphosis. Such effects are remarkably similar in metamorphosing insects and in the brain with AD. In insects, the administration of farnesol/JH temporarily prevents all mentioned changes. The absence of farnesol/JH was not observed in insects with incomplete metamorphosis; hence, there is no massive apoptosis. Neither do vertebrates have a period in their development in which the mevalonate biosynthetic pathway—that synthesizes farnesyl pyrophosphate, farnesol, and cholesterol— comes to a complete halt. Hence, there exists a difficulty in uncovering the other functions of farnesol, besides being an intermediate in the mevalonate pathway. A major breakthrough was achieved in 1999 with the discovery that farnesol in rodent and human brains potently blocks N-type Ca2+ channels. It was proved that the mevalonate pathway and farnesol play key roles in Ca2+ homeostasis. This paper highlights the major consequences of this chemical/pathway in AD research.