Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.
Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined.
Goodman
Ann B
AB
The Massachusetts Mental Health Center Academic Division of Public Psychiatry, Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. annbgoodman@aol.com
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D002877:Chromosomes, Human; D020022:Genetic Predisposition to Disease; D006801:Humans; D005810:Multigene Family; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*
C101326:RBP4 protein, human; D018168:Receptors, Retinoic Acid; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D014212:Tretinoin