TY  - JOUR
AU  - Loof, Arnold De
AU  - Schoofs, Liliane
PY  - 2019
DA  - 2019/11/29
TI  - Alzheimer’s Disease: Is a Dysfunctional Mevalonate Biosynthetic Pathway the Master-Inducer of Deleterious Changes in Cell Physiology?
JO  - OBM Neurobiology
SP  - 046
VL  - 03
IS  - 04
AB  - The awareness is growing that the proteins amyloid-beta (Aβ) and tau are rather a result of Alzheimer’s disease (AD) than its cause. Similarly, doubt reigns about the degree of causality of high plasma cholesterol/lipids (the fat connection) and of prenylation.   An important conceptual addition to the current lines of thinking is advanced here. It emerged from a comparative analysis, in evolutionary retrospect, of the characteristics of the  mevalonate biosynthetic pathways in insects versus in vertebrates/mammals, and of the drastic effects of a declining titer of farnesol and, where present, 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, cause  massive apoptosis in specific tissues, etc. These effects were already observed in insects in the 1960-70ties, when it became undeniably established that the fall to zero of the titer of the 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 AD brain. In insects, administration of farnesol/JH temporarily prevents all cited changes. No such fall to zero in insects with incomplete metamorphosis, hence no massive apoptosis. Neither do vertebrates/mammals have a period in their development in which the mevalonate biosynthetic pathway in which farnesylpyrophosphate, farnesol and cholesterol are synthesized (in their brain inclusive), comes to a complete halt. Hence the difficulty of uncovering functions of farnesol itself other than just serving as an intermediate in the mevalonate pathway. The discovery (1999) that in the rodent and human brain farnesol potently blocks N-type Ca2+ channels, proving that the mevalonate pathway and farnesol play a key role in Ca2+-homeostasis, was a major breakthrough. This paper highlights its major consequences for AD research.
SN  - 2573-4407
UR  - https://doi.org/10.21926/obm.neurobiol.1904046
DO  - 10.21926/obm.neurobiol.1904046
ID  - Loof2019
ER  -