Evidence for defective retinoid transport and function in late onset Alzheimer's disease

Abstract

The hypothesis of this article is that late onset Alzheimer's disease (AD) is influenced by the availability in brain of retinoic acid (RA), the final product of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and environmental͞dietary evidence is cited supporting this hypothesis. Significant genetic linkages to AD are demonstrated for markers close to four of the six RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. Synthesis of the evidence supports retinoid hypofunction and impaired transport as contributing factors. These findings suggest testable experiments to determine whether increasing the availability of retinoid in brain, possibly through pharmacologic targeting of the RA receptors and the cytochrome P450 RAinactivating enzymes, can prevent or decrease amyloid plaque formation.

Vitamine A et vieillissement cérébral

“…Une diminution de la concentration de retinol serique a, par ailleurs, ete revelee chez les patients Alzheimer, ainsi qu'une diminution de l'expression et de l'activite de la retinaldehyde desydrogenase, enzyme impliquee dans la production de l'AR. Une diminution de la biodisponibilite de l'AR liee a l'âge ou a la deregulation de genes codant pour des proteines du metabolisme des retinoïdes et entraînant des alterations dans l'expression de genes cibles de ceux-ci, pourrait alorsêtre fortement impliquee dans l'etiologie de la forme tardive (ou sporadique) de la MA (Goodman et Pardee 2003 ;Goodman, 2006). Les transporteurs de la vitamine A et la MA L'apolipoproteine E (ApoE), apolipoproteine majeure du liquide cerebrospinal, participerait en complement de RBP au transport du retinol et des retinyl esters dans le cerveau.…”

Synthesis of [11C]Bexarotene by Cu-Mediated [11C]Carbon Dioxide Fixation and Preliminary PET Imaging

“…2 Defective retinoid signaling and deficiency of apolipoprotein E (ApoE) are closely associated with Alzheimer's disease (AD). 3 Bexarotene (4-[1- (3,5,5,8,8-pentamethyltetralin-2-yl)-ethenyl]benzoic acid, Figure 1), an FDA-approved selective RXR agonist, 4 has recently been demonstrated to induce clearance of β-amyloid from the brains of murine AD models through activation of the APOE gene, which is the most indicative genetic risk factor for late-onset AD. 5 In vitro and in vivo studies also suggest that bexarotene is acting on RXRs, and not directly on β-amyloid or by compromising the blood−brain barrier.…”

“…When radioactivity had peaked, gas flow was halted, and the vial was sealed and heated to 100°C for 5 min. The reaction mixture was then quenched with 1 mL of HPLC mobile phase (80% CH 3 …”

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

“…Furthermore, dysfunction of retinoid signaling pathway has been hypothesized to be involved in human neurodevelopmental pathologies such as schizophrenia or late-onset Alzheimer's disease (for review, Goodman, 1998Goodman, , 2006Goodman and Pardee, 2003;Palha and Goodman, 2006).…”