2A, row 3). degeneration, and improved spatial learning and memory space compared with the vehicle-treated APP/PS1 mice. These results support ATRA as an effective restorative agent for the prevention and treatment of AD. Keywords:retinoic acid, Alzheimer’s disease, neurodegeneration, -amyloid, memory space, amyloid precursor protein == Intro == Alzheimer’s disease (AD) is the most common form of dementia in the Vicagrel elderly. This disease is usually characterized by extracellular neuritic plaques composed of fibrillar -amyloid (A) peptide and intracellular neurofibrillary tangles made up of hyperphosphorylated tau (Selkoe, 2001). A peptides are generated by successive proteolysis of -amyloid precursor protein (APP), a large transmembrane glycoprotein that is initially cleaved by the -site APP-cleaving enzyme 1 (BACE1) and subsequently by -secretase in the transmembrane domain name (De Strooper et al., 1998;Vassar et al., 1999;Edbauer et al., 2003). Phosphorylation of APP at its C-terminal Thr668 facilitates its processing (Cruz et al., 2006). Although the aggregated A peptides are believed to play a central role in AD pathology (Chen et al., 2000;Apelt and Schliebs, 2001;Gtz et al., 2001;Walsh et al., 2002), the cause of AD remains elusive. Thus, the development of novel therapeutic approaches is usually desperately needed. Retinoic acid (RA), the active metabolite of vitamin A (retinoid), has been shown to control the expression of genes related to APP processing (Lahiri et al., 1995;Yang et al., 1998;Hong et al., 1999;Culvenor et al., 2000;Satoh and Kuroda, 2000). RA regulates gene expression through its nuclear receptors: the RA receptors (RARs) and retinoid X receptors (RXRs) (Mangelsdorf and Evans, 1995). Deprivation of vitamin A results in A accumulation (Corcoran et al., 2004), loss of hippocampal long-term potentiation (LTP) (Misner et al., 2001), and memory deficits in rodents (Cocco et al., 2002;Etchamendy et al., 2003), all of which are hallmarks of AD. Mice that carry mutated versions of RAR Rabbit polyclonal to LeptinR and/or RXR receptors also show deficits in spatial learning and memory (Chiang et al., 1998;Wietrzych et al., 2005). The impairment in spatial learning and memory and the depressive disorder of synaptic plasticity that occurs in vitamin A-deprived rodents also occur during aging in rodents (Etchamendy et al., 2001). Both effects are reversed by the administration of RA (Etchamendy et al., 2001,2003). Importantly, clinical evidence has shown defective retinoid transport and function in AD brain (Goodman and Pardee, 2003), suggesting that increasing the availability of RA in Vicagrel the brain may prevent or decrease A-associated neurodegeneration (Goodman and Pardee, 2003;Goodman, 2006;Maden, 2007). However, to date, there has been no conclusive experimental evidence obtained from AD animal models to show a therapeutic effect of RA on AD. In the present study, we examined the effect of all-transRA (ATRA) treatment around the neurodegenerative pathology and memory deficits in APP and presenilin 1 (PS1) double-transgenic mice, a well Vicagrel established AD mouse model (Moolman et al., 2004;Trinchese et al., 2004;Zhang et al., 2005). When systemically administered to 5-month-old APP/PS1 mice for 8 weeks, ATRA effectively reduced A accumulation and tau hyperphosphorylation. More intriguingly, ATRA treatment of the APP/PS1 mice significantly Vicagrel alleviated glial activation and neuronal loss in the brain and rescued the spatial learning and memory deficits. == Materials and Methods == == == == == == Transgenic mice and ATRA treatment. == APP/PS1 double-transgenic mice used in this study were obtained from The Jackson Laboratory [strain name, B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J; stock number 004462]..