Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β-and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.

Stroke is one of the leading causes of death and disability worldwide, and ischemic stroke accounts for approximately 87% of cases. Improving post-stroke recovery is a major challenge in stroke treatment. Accumulated evidence indicates that the apelinergic system, consisting of apelin and apelin receptor (APLNR), is temporally dysregulated in ischemic stroke. Moreover, the apelinergic system plays a pivotal role in post-stroke recovery by inhibiting neuronal apoptosis and facilitating angiogenesis through various molecular pathways. In this review article, we summarize the temporal expression of apelin and APLNR in ischemic stroke and the mechanisms of their dysregulation. In addition, the protective role of the apelinergic system in ischemic stroke and the underlying mechanisms of its protective effects are discussed. Furthermore, critical issues in activating the apelinergic system as a potential therapy will also be discussed. The aim of this review article is to shed light on exploiting the activation of the apelinergic system to treat ischemic stroke.

Individuals with Down syndrome (DS) will inevitably developAlzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the upregulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knock-out of caspase-3 in caspase-3 ؊/؊ neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress-and A␤-induced neuronal death, and overexpression of RCAN1 due to an extra copy of the RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS. Down syndrome (DS)4 is the most common genetic cause of mental retardation, affecting approximately one in 800 -1,000 babies (1). Individuals with DS inevitably develop characteristic Alzheimer disease (AD) neuropathology, which includes neuritic plaques, neurofibrillary tangles, and neuronal cell death following middle age (2-5). DS is a valuable model system for understanding AD pathogenesis. Both DS and AD feature prominent neuronal losses in the hippocampus and cortex, resulting in progressive cognitive deficits in AD patients (5). Apoptosis has been implicated in playing a major role in neuronal cell death in both AD and DS (6 -9). Increased immunoreactivity of activated caspase-3 is observed in neurons of AD and DS (7); however, the underlying mechanism leading to neuronal apoptosis in AD and DS remains elusive.The development of DS is caused by the presence of an extra copy of human chromosome 21 (10, 11). The DSCR1 (Down syndrome critical region 1) gene was identified and located on chromosome 21 (12, 13). Dysregulation of a regulatory circuit involving DSCR1-calcineurin-nuclear factor of activated T cells (NFAT) plays an important role in DS development (14). DSCR1 proteins physically interact with calcineurin subunit A and inhibit calcineurin activity in vitro and in vivo (15-19). DSCR1 was accordingly renamed as RCAN1 (regulator of calcineurin 1) (20). RCAN1 is phosphorylated at Ser 112 by BMK1 (big MAP kinase 1), which is the priming site for the subsequent phosphorylation at Ser 108 by GSK-3 (21-24). The phosphorylation form of RCAN1 can release the inhibition effect on calcineurin. Furthermore, phosphorylated RCAN1 is a substrate for calcineurin (79). RCAN1 FLISPP motif phosphorylation could increase its ab...

Human telomeres are associated with ATM and the protein complex consisting of MRE11, RAD50 and NBS1 (MRN), which are central to maintaining genomic stability. Here we show that when targeted to telomeres, wild-type RAD50 downregulates telomeric association of TRF1, a negative regulator of telomere maintenance. TRF1 binding to telomeres is upregulated in cells deficient in NBS1 or under ATM inhibition. The TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres. The ability of TRF1 to interact with telomeric DNA in vitro is impaired by ATM-mediated phosphorylation. We propose that MRN is required for TRF1 phosphorylation by ATM and that such phosphorylation results in the release of TRF1 from telomeres, promoting telomerase access to the ends of telomeres.

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is the leading cause of dementia. Neuritic plaque, one of the major characteristics of AD neuropathology, mainly consists of amyloid β (Aβ) protein. Aβ is derived from amyloid precursor protein (APP) by sequential cleavages of β- and γ-secretase. Although APP upregulation can promote AD pathogenesis by facilitating Aβ production, growing evidence indicates that aberrant post-translational modifications and trafficking of APP play a pivotal role in AD pathogenesis by dysregulating APP processing and Aβ generation. In this report, we reviewed the current knowledge of APP modifications and trafficking as well as their role in APP processing. More importantly, we discussed the effect of aberrant APP modifications and trafficking on Aβ generation and the underlying mechanisms, which may provide novel strategies for drug development in AD.