Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein

Nishimura, Isao; Uetsuki, Taichi; Kuwako, Ken-ichiro; Hara, Toshiaki; Kawakami, Toru; Aimoto, Saburo; Yoshikawa, Kunio

doi:10.1038/sj.cdd.4400931

Cited by 35 publications

(12 citation statements)

References 44 publications

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“…Chromosomal DNA was stained with 5 M Hoechst 33342 (Sigma, St. Louis, MO). For Cdc2 immunohistochemistry, paraffin-embedded 8-m-thick sections were incubated with antibodies against Cdc2 [p34 (17), 1:200; Santa Cruz Biotechnology, Santa Cruz, CA] and activated caspase-3 (ACP3, 1:1000) Nishimura et al, 2002) in PBS containing 0.05% Triton X-100 and 2% normal goat serum at room temperature for 12 h, and with secondary antibodies as above. The Cdc2-immunoreactive cells in folium III, which was readily distinguishable from other cerebellar folia, were counted.…”

Section: Methodsmentioning

confidence: 99%

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Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

Kurita

Kuwajima²,

Nishimura³

et al. 2006

J. Neurosci.

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The cell cycle-regulatory transcription factor E2F1 induces apoptosis of postmitotic neurons in developmental and pathological situations. E2F1 transcriptionally activates many proapoptotic genes including the cyclin-dependent protein kinase cell division cycle 2 (Cdc2). Necdin is a potent mitotic suppressor expressed predominantly in postmitotic neurons and interacts with E2F1 to suppress E2F1-mediated gene transcription. The necdin gene NDN is maternally imprinted and expressed only from the paternal allele. Deletion of the paternal NDN is implicated in the pathogenesis of Prader-Willi syndrome, a genomic imprinting-associated neurodevelopmental disorder. Here, we show that paternally expressed necdin represses E2F1-dependent cdc2 gene transcription and attenuates apoptosis of postmitotic neurons. Necdin was abundantly expressed in differentiated cerebellar granule neurons (CGNs). Neuronal activity deprivation elevated the expression of both E2F1 and Cdc2 in primary CGNs prepared from mice at postnatal day 6, whereas the necdin levels remained unchanged. In chromatin immunoprecipitation analysis, endogenous necdin was associated with the cdc2 promoter containing an E2F-binding site in activity-deprived CGNs. After activity deprivation, CGNs underwent apoptosis, which was augmented in those prepared from mice defective in the paternal Ndn allele (Ndn ϩm/Ϫp ). The levels of cdc2 mRNA, protein, and kinase activity were significantly higher in Ndn ϩm/Ϫp CGNs than in wild-type CGNs under activity-deprived conditions. Furthermore, the populations of Cdc2-immunoreactive and apoptotic cells were increased in the cerebellum in vivo of Ndn ϩm/Ϫp mice. These results suggest that endogenous necdin attenuates neuronal apoptosis by suppressing the E2F1-Cdc2 system.

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Section: Methodsmentioning

confidence: 99%

“…Frozen sections of the cerebellum of ICR mice (SLC, Shizuoka, Japan) at postnatal day 6 (P6) and cultured CGNs were prepared for staining as described previously (Nishimura et al, 1998;Nishimura et al, 2002). Fixed tissues and cells were incubated with primary antibodies against necdin (NC243, 1:500) , Ki67…”

Section: Methodsmentioning

confidence: 99%

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

Kurita

Kuwajima²,

Nishimura³

et al. 2006

J. Neurosci.

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“…APP is a transmembrane protein and its proteolytic processing generates a 39 -42 residue peptides referred to as ␤-amyloid (A␤). A␤ peptides are the primary constituents of amyloid deposits found in the aging brain and have been implicated in the pathogenesis of Alzheimer's disease (AD) and Down syndrome by genetic, pathologic, and biochemical evidence (Selkoe, 2001;Nishimura et al, 2002;Lahiri et al, 2003). Therefore, we also examined APP and A␤ levels in old rat brains developmentally exposed to Pb.…”

Section: Introductionmentioning

confidence: 99%

The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and β-Amyloid in the Aging Brain

Basha¹,

Wei²,

Bakheet³

et al. 2005

J. Neurosci.

331

239

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The fetal basis of adult disease (FeBAD) hypothesis states that many adult diseases have a fetal origin. According to FeBAD, injury or environmental influences occurring at critical periods of organ development could result in "programmatic" changes via alterations in gene expression or gene imprinting that may result in functional deficits that become apparent later in life. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by excessive deposits of aggregated ␤-amyloid (A␤) peptides, which are snippets of the ␤-amyloid precursor protein (APP). The predominately sporadic nature of AD suggests that the environment must play a role in neurodegeneration. To examine latent responses to an environmental agent, we exposed rodents to lead and monitored the lifetime expression of the APP gene. We observed that APP mRNA expression was transiently induced in neonates, but exhibited a delayed overexpression 20 months after exposure to Pb had ceased. This upregulation in APP mRNA expression was commensurate with a rise in activity of the transcription factor Sp1, one of the regulators of the APP gene. Furthermore, the increase in APP gene expression in old age was accompanied by an elevation in APP and its amyloidogenic A␤ product. In contrast, APP expression, Sp1 activity, as well as APP and A␤ protein levels were unresponsive to Pb exposure during old age. These data suggested that environmental influences occurring during brain development predetermined the expression and regulation of APP later in life, potentially altering the course of amyloidogenesis.

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“…Production of C31 is a result of APP cleavage at the caspase site D720 of the C-terminus. Following caspase 3 activation, caspase 3 generates the carboxyl-terminally truncated fragment C31 from APP, which has been shown to be capable of apoptotic injury independent of caspase 3 [165]. Furthermore, caspase-dependent APP cleavage at D720 has also been observed in brains of Alzheimer's disease patients through demonstration of C31 expression [132].…”

Section: Processing Of App By Secretases and Caspasesmentioning

confidence: 98%

“…5). The generation of the C-terminal fragment C31 results from the cleavage of APP at the caspase site D720 of the C-terminus by caspase 3 [165]. Once generated, C31 enhances glycogen synthase kinase-3β expression and tau protein phosphorylation [107].…”

Section: The Forkhead Transcription Factor Glycogen Synthase Kinase-mentioning

confidence: 99%

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Chong

Maiese

2005

Brain Research Reviews

135

121

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More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of β-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3β, Bad, and Bcl-x L . Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.

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Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein

Cited by 35 publications

References 44 publications

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and β-Amyloid in the Aging Brain

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

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