Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane

Kaether, Christoph; Lammich, Sven; Edbauer, Dieter; Ertl, Michaela; Rietdorf, Jens; Capell, Anja; Steiner, Harald; Haass, Christian

doi:10.1083/jcb.200201123

Cited by 174 publications

(191 citation statements)

References 63 publications

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“…To test this, we performed confocal fluorescence time-lapse microscopy with HEK293T cells expressing fluorescently tagged BACE1 (RFP-BACE1) and PS1 (GFP-PS1) together with HA-tagged DOR. The subcellular location of RFP-BACE1 or GFP-PS1 is similar to that reported previously [42,43]. Of interest, we detected a strong colocalization of RFP-BACE1 with GFP-PS1 in the presence of DOR ( Figure 2E, second and third rows versus first row).…”

Section: Dor Activation Leads To Enrichment Of Bace1 and γ-Secretase supporting

confidence: 72%

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

et al. 2010

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Dysregulation of β-site APP-cleaving enzyme (BACE) and/or γ-secretase leads to anomalous production of amyloid-β peptide (Aβ) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that δ-opioid receptor (DOR) promotes the processing of Aβ precursor protein (APP) by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/ receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Aβ production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

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Section: Dor Activation Leads To Enrichment Of Bace1 and γ-Secretase supporting

confidence: 72%

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

et al. 2010

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“…1J). As a positive control, a rabbit polyclonal serum 5313 was included which has been described previously (Kaether et al ., 2002). In control siRNA‐transfected HEK293T cells, both monoclonal rat antibodies 1D1 and 7H6 precipitated the hAPP ectodomain with a similar efficiency as the polyclonal 5313 serum.…”

Section: Resultsmentioning

confidence: 99%

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

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SummaryAlzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age‐related and brain region‐specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP‐transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP‐transgenic mouse and one APP‐transgenic rat model. We observed remarkable differences in expression levels and brain region‐specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP‐transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals.

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“…Additionally, fibroblasts derived from nicastrin knock-out mice failed to generate Aβ peptide as a consequence of destabilized γ-secretase complex, thus indicating significance of nicastrin in regulating the γ-secretase activity [31]. Studies from biochemical approaches such as RNAi and protein overexpression have indicated that nicastrin may first bind to APH-1 to form a nicastrin-APH-1 subcomplex prior to its association with PS1 and PEN-2 [11,23,56]. Nevertheless, biogenesis, maturation, stability and the steady-state levels of γ-secretase components are co-dependent.…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane

Cited by 174 publications

References 63 publications

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

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