2010
DOI: 10.4061/2010/825918
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Modeling Presenilin-Dependent Familial Alzheimer's Disease: Emphasis on Presenilin Substrate-Mediated Signaling and Synaptic Function

Abstract: Mutations in PSEN genes, which encode presenilin proteins, cause familial early-onset Alzheimer's disease (AD). Transgenic mouse models based on coexpression of familial AD-associated presenilin and amyloid precursor protein variants successfully mimic characteristic pathological features of AD, including plaque formation, synaptic dysfunction, and loss of memory. Presenilins function as the catalytic subunit of γ-secretase, the enzyme that catalyzes intramembraneous proteolysis of amyloid precursor protein to… Show more

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Cited by 9 publications
(8 citation statements)
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References 156 publications
(189 reference statements)
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“…Here we describe a novel knock‐in model based on a Leu to Pro mutation at codon 166 in PSEN1 that causes a very aggressive form of FAD at an early age (11, 22), leading to a significant increase in Aβ production in cell culture (22, 23) and very strong amyloid deposition in a double‐transgenic model (24). As reported for other Psen1‐knock‐in models, heterozygous and homozygous Psen1‐L166P‐knock‐in mice are viable and overtly healthy for up to 24 mo of age (6–10), although embryonic lethality has recently been reported in a homozygous Psen1‐knock‐in model [R278I (+ / +)] at embryonic day 15–18, similarly to what has been reported for Psen1‐knockout mice. The lethality observed in Psen1‐R278I (+ / +) mice may be due to the abnormal PS1 endoproteolysis seen in these mice, probably leading to problems with Notch1 processing and Notch1 signaling (25).…”
Section: Discussionmentioning
confidence: 55%
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“…Here we describe a novel knock‐in model based on a Leu to Pro mutation at codon 166 in PSEN1 that causes a very aggressive form of FAD at an early age (11, 22), leading to a significant increase in Aβ production in cell culture (22, 23) and very strong amyloid deposition in a double‐transgenic model (24). As reported for other Psen1‐knock‐in models, heterozygous and homozygous Psen1‐L166P‐knock‐in mice are viable and overtly healthy for up to 24 mo of age (6–10), although embryonic lethality has recently been reported in a homozygous Psen1‐knock‐in model [R278I (+ / +)] at embryonic day 15–18, similarly to what has been reported for Psen1‐knockout mice. The lethality observed in Psen1‐R278I (+ / +) mice may be due to the abnormal PS1 endoproteolysis seen in these mice, probably leading to problems with Notch1 processing and Notch1 signaling (25).…”
Section: Discussionmentioning
confidence: 55%
“…Increased levels of AβPP CTFs were reported in cells transfected with PSEN1‐L166P (22, 23) and may result from a reduced γ‐secretase activity rather than from an increase in α‐ and β‐secretase processing of AβPP since both AβPP CTFs increase approximately in the same extent, in both the cerebral cortex and hippocampus (34, 35). The pathological consequence of the accumulation of AβPP CTFs (observed in this model and in patients with AD) is still not completely understood, since accumulation of CTFs may lead to abnormal intracellular signaling and synapse function (6). In addition, accumulated AβPP CTFβs could later be processed by γ‐secretase generating Aβ leading to additional aggregation (36) or generate CTFγ (AβPP intracellular domain), which can cause neuronal dysfunction and tau hyperphosphorylation (37, 38).…”
Section: Discussionmentioning
confidence: 99%
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“…Signal peptide proteases (SPP) and presenilins are representative aspartic intramembrane proteases. Presenilins maintain the activity of the γ-secretase complex, which is involved in the pathogenesis of Alzheimer's disease (Parent and Thinakaran 2010). In mammalian cells, the basic γ-secretase subunits include four integral membrane proteins: presenilin 1 (Ps1) or presenilin 2 (Ps2), APH-1a or APH-1b, PEN-2, and nicastrin (Nct) (Fraering et al 2004;De Strooper and Annaert 2010;Gertsik et al 2015;Sun et al 2015).…”
Section: Introductionmentioning
confidence: 99%
“…Moreover, some PS mutations have been connected to Reelin signaling elements such as PI3-kinase and Crk/Dock1/Rac (Chen et al, 2004; Parent Thinakaran, 2010; Qiu et al, 2006), which suggests that part of the effect of PS mutation on synaptic processes could be related to Reelin receptors such as apoER2. We have initiated studies of the impact of FAD PSEN1 mutations on the processing and trafficking of apoER2.…”
Section: Introductionmentioning
confidence: 99%