title: Rescue of Hypovitaminosis A Induces Non-Amyloidogenic Amyloid Precursor Protein (APP) Processing.
abstract: Retinoic acid, the bioactive metabolite of beta-carotene or vitamin A, plays a pleiotropic, multifunctional role in vertebrate development. Studies in rodents revealed that a diet deficient in vitamin A results in a complex neonatal syndrome (the VAD syndrome), manifested in many organs. In humans, the function of retinoic acid (RA) extends into adulthood, where it has important roles in fertility, vision, and suppression of neoplastic growth. In recent years, it has also been suggested that retinoic acid might potentially act as a therapeutically relevant drug in attenuating or even preventing neurodegenerative diseases such as Alzheimer's disease (AD). Here, we report that VAD leads to an increase in A-beta peptide levels while only minor effects were observed on expression levels of the amyloid precursor protein (APP) processing proteinases in wild type mice. In line with these findings, rescue of hypovitaminosis reduced A-beta amount to baseline and induced sApp-alpha secretion in combination with an increase of alpha-secretase Adam10. By comparing retinoic acid treatment starting from a full nutrition status and a "VAD" situation in human neuroblastoma cells, we show that while intensities of differential gene expression were higher in replenished cells, a large overlap in AD-related, regulated genes was observed. Our data suggest that hypovitaminosis A can contribute to onset or progression of AD by increasing synthesis of A-beta peptides and that several AD-related genes such as ADAM10 or BDNF are regulated by retinoic acid. We suggest that dietary supplementation with retinoic acid derivatives is likely to have a beneficial effect on AD-pathology in individuals with hypovitaminosis and patients with normal vitamin A status.
authors.forename: Sven
authors.initials: S
authors.lastname: Reinhardt
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: Christoph
authors.initials: C
authors.lastname: Stahlmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Clinic of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg University Mainz, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism; D017255:Acitretin / Q000737:chemistry / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007641:Keratolytic Agents / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D017208:Rats, Wistar; D014212:Tretinoin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014802:Vitamin A Deficiency / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007641:Keratolytic Agents; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; C078592:amyloid beta-protein (1-40); D014212:Tretinoin; D000072197:ADAM10 Protein; D017255:Acitretin