Reduced β-Amyloid Production and Increased Inflammatory Responses in Presenilin Conditional Knock-out Mice

Beglopoulos, Vassilios; Sun, Xiaoyan; Saura, Carlos A.; Lemere, Cynthia A.; Kim, Richard D.; Shen, Jie

doi:10.1074/jbc.m409544200

Cited by 148 publications

(125 citation statements)

References 35 publications

(56 reference statements)

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“…In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8)(9)(10)(11)(12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14).…”

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confidence: 72%

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short-and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca 2+ in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca 2+ homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short-and longterm synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The majority of familial AD cases are caused by missense mutations in genes encoding presenilin 1 (PS1) and presenilin 2, which are crucial components of the γ-secretase complex responsible for intramembrane cleavages of type I membrane proteins such as Notch. In addition to presenilin (PS), nicastrin (Nct), presenilin enhancer 2 (Pen-2), and anterior pharynx defective 1 (Aph-1) also are required to form the active γ-secretase complex. Nct is a type-1 transmembrane glycoprotein that originally was identified by its ability to form high molecular weight complexes with PS (1). Nct −/− mice die by embryonic day 10.5 and exhibit patterning defects similar to those in embryos lacking PS or Notch (2-7).In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8-12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14). However, Notch is unlikely to be the key mediator of γ-secretase in the adult brain, because Notch1 and Notch2 conditional knockout (cKO)...

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confidence: 72%

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Immunohistochemical analysis revealed striking up-regulation of cathepsin S and complement C1q (Fig. 4 D and E), widely used markers for inflammatory responses (26,27), in kidneys of LRRK2 −/− mice at 20 months of age, whereas levels of these markers in kidneys of LRRK2 −/− mice at 10 weeks of age were normal. Western analysis also confirmed the increases in the levels of cathepsin S and C1q in kidneys of 20-month-old LRRK2 −/− mice (Fig.…”

Section: Accumulation and Aggregation Of α-Synuclein And Ubiquitinatedmentioning

confidence: 99%

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Tong

Yamaguchi

Giaime

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2 −/− mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2 −/− kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.Parkinson's disease | knockout | autophagy | ubiquitin-proteasome system | aging P arkinson's disease (PD) is the most common movement disorder. The neuropathological hallmarks of PD are progressive degeneration of dopaminergic (DA) neurons and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies, of which α-synuclein is a major constituent (1). Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial PD (2, 3), highlighting the importance of LRRK2 in PD pathogenesis; however, the normal physiological role of LRRK2 is unknown. LRRK2 is a large protein containing a Ras-like small GTPase domain and a MAPKKK-like kinase domain, and has a functional homolog LRRK1, which shares similar domain structures (4). Crystal structural and biochemical studies showed that the GTPase domain forms a dimer; the pathogenic mutations destabilize the dimer and reduce GTPase activity (5-7). A recent in vitro study suggested that LRRK2 and LRRK1 can interact with each other and form a heterodimer (8). Although no physiological substrate of the LRRK2 kinase activity has been reported, studies in cultured cells have suggested that some pathogenic mutations in LRRK2 cause increases in LRRK2 kinase activity (9, 10).Protein aggregation is thought to play a major role in neurodegeneration and PD pathogenesis (11). The strongest evidence came from studies of α-synuclein. Gene multiplication and missense mutations in α-synuclein have been identified in early-onset familial PD with dominant inheritance (12). α-Synuclein is a major constituent of Lewy bodies (1). Overexpression of either WT or mutant α-synuclein in transgenic mice causes age-related neurodegeneration (13-15). Although patients carryi...

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“…It has been reported that Aβ production was reduced in PS1/PS2 conditional double knockout mice (cDKO) [12] . Although our dKO mice are also forebrain knockout of PS1/ PS2, there are two differences between dKO and cDKO.…”

Section: Discussionmentioning

confidence: 99%

“…Although our dKO mice are also forebrain knockout of PS1/ PS2, there are two differences between dKO and cDKO. One is the different loxP insert site on PS1 allele, and the other is that these two strains of PS1/PS2 conditional knockout mice are generated by two separate research groups and are maintained in different conditions [2,9,12,26] . To examine the Aβ level in our dKO mice, we evaluated protein level of Aβ 42 using ELISA assay for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…It is supposed that knockout of both PS1 and PS2 may reduce the production of Aβ, thus delay or prevent the onset of AD. Interestingly, while the forebrain-specific conditional PS1 and PS2 double knockout mice (dKO mice) indeed showed decreased Aβ content, they also exhibited several Alzheimer-like neurodegenerative symptoms, including impairments in both synaptic plasticity and hippocampus-dependent memory, severe shrinkage of the cortex, neuronal atrophy, tau phosphorylation and enlargement of the lateral and third ventricles [2,3,12] .…”

Section: Introductionmentioning

confidence: 99%

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Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

Zhang¹,

Chen²,

Xu³

et al. 2009

Neurosci. Bull.

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Objective This report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice. Methods The protein level of Aβ 42 in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately. Results Significant decrease of Aβ 42 was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months. Conclusion Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Aβ 42 . Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.

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Reduced β-Amyloid Production and Increased Inflammatory Responses in Presenilin Conditional Knock-out Mice

Cited by 148 publications

References 35 publications

Synaptic function of nicastrin in hippocampal neurons

Synaptic function of nicastrin in hippocampal neurons

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

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