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The Journal of Neuroscience, November 5, 2008, 28(45):11622-11634; doi:10.1523/JNEUROSCI.3153-08.2008

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Neurobiology of Disease
Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Yun Ding,^1,2 Aimin Qiao,⁴ Ziqing Wang,² J. Shawn Goodwin,⁵ Eun-Sook Lee,⁴ Michelle L. Block,³ Matthew Allsbrook,² Michael P. McDonald,⁶ and Guo-Huang Fan^1,2

¹Department of Veterans Affairs Medical Center, Richmond, Virginia 23249, Departments of ²Pharmacology and Toxicology and ³Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, Departments of ⁴Neurobiology and Neurotoxicology and ⁵Cancer Biology, Meharry Medical College, Nashville, Tennessee 37208, and ⁶Department of Neurology, the University of Tennessee Health Science Center, Memphis, Tennessee 38163

Correspondence should be addressed to Dr. Guo-Huang Fan, Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. Email: ghfan{at}vcu.edu

Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to β-amyloid (Aβ) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain Aβ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

Key words: retinoic acid; Alzheimer's disease; neurodegeneration; β-amyloid; memory; amyloid precursor protein

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Received July 8, 2008; revised Aug. 28, 2008; accepted Sept. 10, 2008.

Correspondence should be addressed to Dr. Guo-Huang Fan, Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. Email: ghfan{at}vcu.edu

This article has been cited by other articles:

				N. Ghenimi, M.-C. Beauvieux, M. Biran, V. Pallet, P. Higueret, and J.-L. Gallis Vitamin A Deficiency in Rats Induces Anatomic and Metabolic Changes Comparable with Those of Neurodegenerative Disorders J. Nutr., April 1, 2009; 139(4): 696 - 702. [Abstract] [Full Text] [PDF]

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