After rinsing with deionized water, they were dehydrated and mounted with Permount (Daigger, IL USA). a neuron-specific expression of human EID1 gene in the brain. Overexpression of EID1 led to an increase in its nuclear localization in neurons mimicking that seen in human AD brains. The transgenic mice experienced a disrupted neurofilament business and increase of astrogliosis in the cortex and hippocampus. Furthermore, we exhibited that overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function in the transgenic mice. Our results indicated that this negative effects of extra nuclear EID1 in transgenic mouse brains are likely due to its inhibitory function on CBP/p300 mediated histone and p53 acetylation, thus affecting the expression of downstream genes involved in the maintenance of neuronal structure and function. Together, our data raise the possibility that alteration of EID1 expression, particularly the increase of EID1 nuclear localization that inhibits CBP/p300 activity in neuronal cells, may play an important role in AD pathogenesis. Keywords:EP300 interacting inhibitor of differentiation 1, CBP/p300, histone, p53, Acetylation, Alzheimers disease == Introduction == EID1 (EP300 interacting inhibitor of differentiation1), also known as CRI1, was originally identified as JDTic a pRb-interacting protein negatively regulates myogenesis (MacLellan et al., 2000;Miyake et al., 2000). EID1 inhibits myogenic differentiation by blocking the histone acetyltransferase (HAT) activity of p300/CREB (cAMP response element binding protein) binding protein, a transcriptional co-activator, required for hEDTP MyoD dependent transactivation. Its physical conversation with pRb brings EID1 to MDM2, an E3 ubiquitin ligase, leading to its proteasomal degradation up on cell cycle exit. In contrast, its conversation with the RET finger protein (RFP, TRIM 27), an upstream modulator JDTic of Rb, increases the stability of EID1protein thus inhibits Rb mediated transcription activation (Krutzfeldt et al., 2005). A newly recognized EID1 binding partner, Necdin, antagonizes the repressive effects of EID1 whereby promotes myoblast differentiation. This conversation also stabilizes EID1 and promotes its relocalization to the cytoplasm (Bush and Wevrick, 2008). EID1 can also be recruited and bridged by other transcriptional inhibitors, such as small heterodimer partner (SHP), which directly binds and inhibits JDTic a large set of nuclear receptors, or bind directly to nuclear receptors, such as orphan nuclear receptor, SF1, to accomplish transcriptional inhibition (Bavner et al., 2002;Macchiarulo et al., 2006;Park et al., 2007). It is suggested that the mechanism of these transcriptional inhibitions entails EID1 antagonism of the p300/CBP (CREB binding protein)-dependent co-activator functions (Bavner et al., 2002;Chen et al., 2005;Park et al., 2007). Transcriptional co-activator CBP and p300 have high degree of homology and comparable pattern of expression. They both stimulate CREB-dependent gene expression by interacting with and integrating a variety of signal-responsive transcription factors, modifying transcription factors and histone by acetylation (Vo and Goodman, 2001). Their co-activator functions regulate many physiological processes including cell growth, differentiation and apoptosis. Therefore, CBP/p300 promoted signaling mechanism is usually important for long-term memory and neuronal survival (Maggirwar et al., 2000;Yukawa et al., 1999;Alarcon et al., 2004). Mutations and decreased levels of CBP/p300 are associated with a number of neurological disorders including Rubinstein-Taybi Syndrome (RTS) and Spinocerebellar ataxia type 1 (SCA1) (Roelfsema et al., 2005;Tsirigotis et al., 2006). Loss of function in CBP/p300 has been directly associated with familial Alzheimers disease (FAD) (Francis et al., 2007;Marambaud et al., 2003) and crucial loss of CBP/p300 histone acetylase activity has been linked to neuronal apoptosis (Rouaux et al., 2003). FAD related studies have exhibited that mutations in APP and PS1 alter CBP/CREB function. In a cell culture model, Vitolo et al. exhibited a decrease of PKA activity, CREB activation and LTP in hippocampal neurons by A peptide (Vitolo et al., 2002). In a transgenic (Tg) mouse model, mutations of APP and PS1 were associate with CBP/CREB dysfunction (Gong et al., 2004). Treatments by rolipram that augment cAMP/CREB signaling enhances LTP and memory function in the mouse model. In a conditional knockout mouse model, in which PS1/2 is usually selectively inactivated in excitatory neurons, there is a decrease of CBP and a reduction of JDTic transcription of CBP/CREB genes. Consequently, the conditional knockout mice have LTP and memory deficiency as they are aging (Saura et al., 2004). EID1 has been identified as an inhibitor of p300 by suppression of the acetyltransferase activity during myogenesis. Its function in other tissues or cell type has not been elucidated. EID1 transcripts are ubiquitously detected in human tissues with best expression in cardiac and skeletal muscle mass and brain (MacLellan et al., 2000;Miyake et al., 2000), and has exceptionally high level of expression in mouse brain (Bavner et al., 2002). We were intrigued by this expression pattern especially since EID1 is usually reported to be degraded upon cell cycle exit in skeletal muscle mass, thus expected to show comparable behaviors in neuronal differentiation and low levels of JDTic expression in terminally differentiated neurons. We set out to investigate.