[show abstract][hide abstract] ABSTRACT: Serine-arginine protein kinases 2 (SRPK2) is a cell cycle-regulated kinase that phosphorylates serine/arginine domain-containing proteins and mediates pre-mRNA splicing with unclear function in neurons. Here, we show that SRPK2 phosphorylates tau on S214, suppresses tau-dependent microtubule polymerization, and inhibits axonal elongation in neurons. Depletion of SRPK2 in dentate gyrus inhibits tau phosphorylation in APP/PS1 mouse and alleviates the impaired cognitive behaviors. The defective LTP in APP/PS1 mice is also improved after SRPK2 depletion. Moreover, active SRPK2 is increased in the cortex of APP/PS1 mice and the pathological structures of human Alzheimer's disease (AD) brain. Therefore, our study suggests SRPK2 may contribute to the formation of hyperphosphorylated tau and the pathogenesis of AD.
Journal of Neuroscience 11/2012; 32(48):17262-72. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5-7 months of age) and old (25-30 months of age) mice with the four genotypes, wild-type (Sod2(+/+)), hemizygous Sod2 (Sod2(+/-)), hAPP/wild-type (Sod2(+/+)), and hAPP/hemizygous (Sod2(+/-)) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2(+/+) or Sod2(+/-). Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2(+/-) mice may contribute to the pathological and behavioral changes seen in this animal model.
PLoS ONE 01/2012; 7(1):e28033. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: In Alzheimer disease (AD), amyloid-β (Aβ) oligomer is suggested to play a critical role in imitating neurodegeneration, although its pathogenic mechanism remains to be determined. Recently, the cellular prion protein (PrP(C)) has been reported to be an essential co-factor in mediating the neurotoxic effect of Aβ oligomer. However, these previous studies focused on the synaptic plasticity in either the presence or the absence of PrP(C) and no study to date has reported whether PrP(C) is required for the neuronal cell death, the most critical element of neurodegeneration in AD. Here, we show that Prnp(-/-) mice are resistant to the neurotoxic effect of Aβ oligomer in vivo and in vitro. Furthermore, application of an anti-PrP(C) antibody or PrP(C) peptide prevents Aβ oligomer-induced neurotoxicity. These findings are the first to demonstrate that PrP(C) is required for Aβ oligomer-induced neuronal cell death, the pathology essential to cognitive loss.
Human Molecular Genetics 11/2011; 21(5):1138-44. · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neuronal cell cycle activation has been implicated in neurodegenerative diseases such as Alzheimer's disease, while the initiating mechanism of cell cycle activation remains to be determined. Interestingly, our previous studies have shown that cell cycle activation by c-Myc (Myc) leads to neuronal cell death which suggests Myc might be a key regulator of cell cycle re-entry mediated neuronal cell death. However, the pattern of Myc expression in the process of neuronal cell death has not been addressed. To this end, we examined Myc induction by the neurotoxic agents camptothecin and amyloid-β peptide in a differentiated SH-SY5Y neuronal cell culture model. Myc expression was found to be significantly increased following either treatment and importantly, the induction of Myc preceded neuronal cell death suggesting it is an early event of neuronal cell death. Since ectopic expression of Myc in neurons causes the cell cycle activation and neurodegeneration in vivo, the current data suggest that induction of Myc by neurotoxic agents or other disease factors might be a key mediator in cell cycle activation and consequent cell death that is a feature of neurodegenerative diseases.
[show abstract][hide abstract] ABSTRACT: Nuclear fragmentation is a common feature in many neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we show that nuclear lamina dispersion is an early and irreversible trigger for cell death initiated by deregulated Cdk5, rather than a consequence of apoptosis. Cyclin-dependent kinase 5 (Cdk5) activity is significantly increased in AD and contributes to all three hallmarks: neurotoxic amyloid-β (Aβ), neurofibrillary tangles (NFT), and extensive cell death. Using Aβ and glutamate as the neurotoxic stimuli, we show that deregulated Cdk5 induces nuclear lamina dispersion by direct phosphorylation of lamin A and lamin B1 in neuronal cells and primary cortical neurons. Phosphorylation-resistant mutants of lamins confer resistance to nuclear dispersion and cell death on neurotoxic stimulation, highlighting this as a major mechanism for neuronal death. Rapid alteration of lamin localization pattern and nuclear membrane change are further supported by in vivo data using an AD mouse model. After p25 induction, the pattern of lamin localization was significantly altered, preceding neuronal death, suggesting that it is an early pathological event in p25-inducible transgenic mice. Importantly, lamin dispersion is coupled with Cdk5 nuclear localization, which is highly neurotoxic. Inhibition of nuclear dispersion rescues neuronal cells from cell death, underscoring the significance of this event to Cdk5-mediated neurotoxicity.
Molecular biology of the cell 03/2011; 22(9):1452-62. · 5.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease. A considerable need exists for the development of an effective therapy to prevent, or at least delay, the progression of AD. Current hypotheses for the pathogenesis of AD are discussed in this review, with a particular emphasis on the implications of these hypotheses with respect to treatment strategies and preventive measures.
Current opinion in drug discovery & development 03/2010; 13(2):235-46. · 5.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cyclin-dependent kinase (Cdk) 5 and p38 activities are significantly increased in Alzheimer's Disease (AD). Both p38 and Cdk5 promote neurodegeneration upon deregulation. However, to date the mechanistic link between Cdk5 and p38 remains unclear. This study presents the first mechanism showing Cdk5 as a major regulator of p38 cascade in neurons and in transgenic mouse model of AD. Using beta-amyloid and glutamate as the neurotoxic stimuli, our results show that deregulated Cdk5 induces p38 activation by increasing reactive oxygen species (ROS) in neuronal cells and in primary cortical neurons. Elimination of ROS inhibits p38 activation, revealing ROS as major stimuli of the p38 cascade. Importantly, Cdk5-mediated p38 activation increases c-Jun expression, thereby revealing a mechanistic link between deregulated Cdk5 and c-Jun level in AD brains. c-Jun is over-expressed in AD, and is believed to contribute significantly to neurodegeneration. Based on the proposed mechanism, Cdk5 inhibition is more neuroprotective relative to p38 and c-Jun, suggesting that Cdk5 is an upstream regulator of neurodegenerative pathways triggered by p38 and a preferable therapeutic target for AD.
Journal of Neurochemistry 03/2010; 113(5):1221-9. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The complex neurodegeneration underlying Alzheimer disease (AD), although incompletely understood, is characterised by an aberrant re-entry into the cell cycle in neurons. Pathological evidence, in the form of cell cycle markers and regulatory proteins, suggests that cell cycle re-entry is an early event in AD, which precedes the formation of amyloid-beta plaques and neurofibrillary tangles (NFTs). Although the exact mechanisms that induce and mediate these cell cycle events in AD are not clear, significant advances have been made in further understanding the pathological role of cell cycle re-entry in AD. Importantly, recent studies indicate that cell cycle re-entry is not a consequence, but rather a cause, of neurodegeneration, suggesting that targeting of cell cycle re-entry may provide an opportunity for therapeutic intervention. Moreover, multiple inducers of cell cycle re-entry and their interactions in AD have been proposed. Here, we review the most recent advances in understanding the pathological implications of cell cycle re-entry in AD.
Expert Reviews in Molecular Medicine 01/2010; 12:e19. · 6.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Brain aging is one of the most complex issues confronting researchers in neuroscience today. Nevertheless, research on the
molecular biology of neurodegenerative disorders, particularly Alzheimer disease, has provided enormous progress in understanding
the mechanisms that ultimately lead to the neuronal and glial malfunctions that ultimately damage neurons resulting in death.
In this regard, one of the most compelling theories providing a basis for understanding aging and neurodegeneration posits
oxidative stress, which results from an accumulation of “free radicals” in the cell that originates from the intense oxidative
metabolism in the central nervous system and the diminished antioxidant defenses, as a major contributor. Here we review evidence
demonstrating a robust relationship—epidemiological-clinical, molecular-neurobiological, and pathogenetic—between brain senility,
mild cognitive impairment, and Alzheimer disease (as well as other neurodegenerative conditions) that places oxidative stress
at a pivotal point in these three neurophysiologic and neuropathologic processes. These observations suggest that the three
conditions are steps in the progressive decline in cognitive function. First, we focus on classical, clinical, and psychiatric
observations of the cognitive ability of elderly people, from normal functioning to declines associated with aging, and then
move to mild and severe pathological impairment, with continually worsening clinical and neuropsychiatric status. We show
that the term “senile dementia”, today removed from the nosological categories, is in fact representative of the clinical
observations of progressive age-related brain deterioration. Second, we address oxidative stress and describe the new neurochemical
and neuropathological theories of disease pathogenesis, that implicate oxidative stress as the earliest process in brain aging
and neurodegeneration in Alzheimer disease. Moreover, we discuss the evidence that amyloid-β, senile plaques, and neurofibrillary
tangles may comprise a compensatory defense mechanism against oxidative stress. In addition, the oxidative stress-amyloid-β
“cascade” that develops during Alzheimer disease is also described, in which amyloid formation in the brain further exposes
neurons to oxidative stress, eliciting a full neurodegenerative response. Finally, we explore how current treatments of Alzheimer
disease, such as acetylcholinesterase inhibitors and non-specific glutamate receptor inhibitors/antagonists, may benefit from
the inclusion of antioxidants or metabolic agents that target brain aging, mild cognitive impairment, Alzheimer disease, and
other neurodegenerative diseases.
KeywordsOxidative stress-Neurodegeneration-Aging-Alzheimer disease-Amyloid-β protein precursor-Mild cognitive impairment-Positron emission tomography-Reactive nitrogen species-Reactive oxygen species
[show abstract][hide abstract] ABSTRACT: Retinoic acid, an essential factor derived from vitamin A, has been shown to have a variety of functions including roles as an antioxidant and in cellular differentiation. Since oxidative stress and dedifferentiation of neurons appear to be common pathological elements of a number of neurodegenerative disorders, we speculated that retinoic acid may offer therapeutic promise. In this vein, recent compelling evidence indicates a role of retinoic acid in cognitive activities and anti-amyloidogenic properties. Here, we review the actions of retinoic acid that indicate that it may have therapeutic properties ideally served for the treatment of neurodegenerative diseases such as Alzheimer's disease.
Expert Review of Neurotherapeutics 11/2009; 9(11):1615-21. · 2.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lipid peroxidation byproducts, such as 4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE), induce cell death in a wide variety of cell types, partly by modulating intracellular signaling pathways. However, the specific mechanisms involved, particularly for ONE, are unclear while c-Jun N-terminal kinase (JNK) has been shown to be essential in HNE-mediated cytotoxicity. In this study, we examined the role of mitogen-activated protein kinases signaling pathways in ONE-induced cytotoxicity in SH-SY5Y human neuroblastoma cells and found that ONE strongly induces the phosphorylation of extracellular signal-regulated kinase (ERK) and JNK, but not p38 MAPK. Interestingly, a transient exposure of the cells to ONE resulted in cell death, which contrasts with HNE-mediated toxicity. Importantly, blocking the ERK pathway, but not the JNK pathway, protected cells against ONE-induced cytotoxicity indicating a striking difference between the ONE- and HNE-mediated cytotoxicity mechanisms. Furthermore, inhibition of ERK reduced ONE-induced phosphorylation of p53, a key modulator of the cellular stress response, and the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), a hallmark of apoptosis. Overall, these data strongly suggest that ERK plays an essential role in ONE-mediated cytotoxicity and that ERK is an upstream component of p53-mediated apoptosis.
Journal of Neurochemistry 02/2009; 108(6):1434-41. · 3.97 Impact Factor