APP Processing and Synaptic Plasticity in Presenilin-1 Conditional Knockout Mice

Yu, Huakui; Saura, Carlos A.; Choi, Se‐Young; Sun, Lillian; Yang, Xudong; Handler, Melissa; Kawarabayashi, Tatsuhiko; Younkin, Linda H.; Fedeles, Bogdan I.; Wilson, Matthew A.; Younkin, Steve; Kandel, Eric R.; Kirkwood, Alfredo; Shen, Jie

doi:10.1016/s0896-6273(01)00417-2

Cited by 239 publications

(265 citation statements)

References 58 publications

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“…1B ) and it is well documented that PS1 generates more Aβ than PS2 [8-18]. Previous work indicates that γ-secretase cleaves APP in a processive manner such that ε-site cleavage (resulting in AICD release) precedes γ-site cleavage (resulting in Aβ release) [25, 37].…”

Section: Discussionmentioning

confidence: 99%

“…In vitro cellular and biochemical studies [8-12], as well as in vivo loss of function studies [13-18] have demonstrated that PS1-containing complexes generate significantly more Aβ peptide from the APP substrate than PS2-containing complexes. As a result, the majority of studies have focused on PS1 in their efforts to better understand γ-secretase biology and to identify ways to inhibit or modulate its activity for the treatment of AD.…”

Section: Introductionmentioning

confidence: 99%

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Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Pintchovski¹,

Basi²

2013

Current Alzheimer Research

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The γ-secretase complex cleaves the carboxy-terminal 99 residue (C99) fragment of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. The catalytic activity of this complex is mediated either by the presenilin-1 (PS1) or the presenilin-2 (PS2) subunit. In vitro and in vivo studies have demonstrated that PS1-containing complexes generate more total Aβ product than PS2-containing complexes, indicating greater cleavage activity by PS1-containing γ-secretase complexes at the APP γ-site. However, it remains untested whether γ-secretase cleavage at the APP ε-site, which precedes γ-site cleavage and produces the physiologically active APP intracellular domain (AICD), follows the same rule. Using a novel Swedish APP-GVP substrate to facilitate the parallel detection of Aβ and AICD products from PS1-/-/PS2-/- cells co-transfected with either PS1 or PS2, we observed that while PS1 generates more total Aβ product than PS2, consistent with published reports, PS1 and PS2 unexpectedly generate equal amounts of AICD product. We also observed that PS1 and PS2 produce equivalent amounts of Notch intracellular domain (NICD), indicating equal cleavage activity at the Notch S3-site (the corollary of the APP ε-site). Our findings suggest that processivity differences between PS1 and PS2 underlie the differential production of Aβ peptide. Taken together these findings offer novel insights into γ-secretase biology and have important implications for therapeutically targeting γ-secretase

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Pintchovski¹,

Basi²

2013

Current Alzheimer Research

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“…This inhibition caused an accumulation of C-terminal fragments of APP and a dramatical decrease in Aβ production. In 2001, PSEN1 conditional knockout mice were created and raised to adulthood [158]. In these animals the levels of C-terminal fragments of APP were 30 times increased as compared to normal, and Aβ40 and Aβ42 peptides were significantly reduced.…”

Section: Transgenic Mouse Models For Eoadmentioning

confidence: 99%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies. KEYWORDS:Alzheimer dementia, neurodegeneration, mutations, linkage analysis, association analysis, mouse models DOMAINS: genetics (man), aging, neuroscience INTRODUCTIONAlzheimer's disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory loss and cognitive decline during mid to late adult life, leading to dementia and ultimately death. AD is the most common form of dementia in the elderly, and represents the fourth largest cause of death in the developed world. In the near future, the impact of AD on our society will dramatically increase since, as populations live longer, the number of elderly people continues to grow.The clinical symptoms of AD display a substantial overlap with clinical symptoms observed in other neurodegenerative disorders with dementia as accompanying feature, such as *Corresponding author. Address: Department of Molecular Genetics (VIB8), Neurogenetics Group, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium; Tel: +32 3 8202601/Fax: +32 3 8202541 ©2003 with author.497 Rademakers et al.: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 frontotemporal dementia (FTD) and Creutzfeldt Jacob's disease (CJD). Therefore a definite diagnosis of AD can only be obtained at autopsy. Extensive neuronal loss, and two particular brain lesions in the cerebral cortex, hippocampus, and amygdala characterize AD: the senile plaques (SPs) and neurofibrillary tangles (NFTs). The SPs are compact extracellular deposits that consist of a large amyloid β (Aβ) core surrounded by dystrophic neurites. NFTs are intraneuronal inclusions of paired helical filaments (PHF) that are mainly composed of hyperphosphorylated microtubule associated protein tau (MAPT).Based on the age at which the first clinical symptoms become...

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“…The PS1-deficient mice generated by the conventional knockout strategy were embryonic lethal (Wong et al, 1997). However, recent studies with a conditional knockout strategy have circumvented the lethality of PS1-deficient mice and generated adult animals lacking PS1 specifically in the brain (Yu et al, 2001b;Dewachter et al, 2002). The study involving these double transgenic mice carrying both the PS1 conditional mutation and the APP V717I transgene revealed that the elimination of the g-secretase activity provided by PS1 markedly reduced Ah production, plaque deposition, and rescued impaired hippocampal LTP but that it did not correct the deficits in learning that APP V717I transgenic mice displayed (Dewachter et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Lee

Song

et al. 2006

Neurobiology of Disease

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APP Processing and Synaptic Plasticity in Presenilin-1 Conditional Knockout Mice

Cited by 239 publications

References 58 publications

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Genetics of Early-Onset Alzheimer Dementia

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

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