HX Xu's research while affiliated with The Rockefeller University and other places
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Publications (10)
A variety of investigations have led to the conclusion that presenilins (PS) play a critical role in intramembranous, γ-secretase
proteolysis of selected type I membrane proteins, including Notch1 and amyloid precursor protein (APP). We now show that the
generation of the S3/Notch intracellular domain and APP-carboxyl-terminal fragment γ (CTFγ) der...
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Release of Aβ peptides from β-amyloid precursor protein (APP) requires sequential cleavage by two endopeptidases, β- and γ-secretases.
β-Secretase was recently identified as a novel membrane-bound aspartyl protease, named BACE1, Asp2, or memapsin 2. Employing
confocal microscopy and subcellular fractionation, we have found that BACE1 is largely sit...
Alzheimer's Disease (AD) is characterized by cerebral accumulation of beta-amyloid peptides (Abeta), which are proteolytically derived from beta-amyloid precursor protein (betaAPP). betaAPP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to...
Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (Abeta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for Abeta in the pathophysiology of AD. Abeta peptides are generated by the regulated cleavage of an approximately 700-aa Abeta precursor protein (...
The Alzheimer's amyloid-β precursor protein (βAPP) is a type 1 membrane-spanning protein from which the Alzheimer's disease
amyloid-β peptide (Aβ) is proteolytically derived. To date, attempts to identify the enzymes responsible for Aβ generation
have failed. Here we report the accumulation of Aβ-immunoreactive peptides in yeast expressing human βA...
The excessive generation and accumulation of 40- and 42-aa beta-amyloid peptides (Abeta40/Abeta42) in selectively vulnerable brain regions is a major neuropathological feature of Alzheimer's disease. Abeta, derived by proteolytic cleavage from the beta-amyloid precursor protein (betaAPP), is normally secreted. However, recent evidence suggests that...
Studies of processing of the Alzheimer beta-amyloid precursor protein (betaAPP) have been performed to date mostly in continuous cell lines and indicate the existence of two principal metabolic pathways: the "beta-secretase" pathway, which generates beta-amyloid (A beta(1-40/42); approximately 4 kDa), and the "alpha-secretase" pathway, which genera...
beta-amyloid protein (A beta) formation was reconstituted in permeabilized neuroblastoma cells expressing human Alzheimer beta-amyloid precursor protein (beta APP) harboring the Swedish double mutation associated with familial early-onset Alzheimer disease. Permeabilized cells were prepared following metabolic labeling and incubation at 20 degrees...
Various compounds that affect signal transduction regulate the relative utilization of alternative processing pathways for the beta-amyloid precursor protein (beta APP) in intact cells, increasing the production of nonamyloidogenic soluble beta APP (s beta APP) and decreasing that of amyloidogenic beta-amyloid peptide. In a recent study directed to...
Citations
... What could account for the increased residence of APP at the surface in our experimental system? Activation of the PKA-dependent pathway is known to stimulate APP trafficking to the surface, through the formation of APP-containing vesicles from the trans-Golgi network (Xu et al., 1996). Although we have not fully explored the mechanisms responsible for greater APP retention at the cell surface beyond mechanisms that involve the cAMPdependent pathway, it is well recognized that downstream phosphorylation signaling events could interfere with protein trafficking at the surface. ...
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... 71−74 Also, the in vivo concentration of 4-HNE is larger than the Aβ concentration (1−10 nM) under physiological or pathophysiological conditions. 75,76 In this regard, we have opted for one of the simplest animal models, C. elegans. The high transparency, shorter lifespan, isogenic nature, and 60%−80% similarity with human genes make C. elegans one of the most widely studied simple model organisms for in vivo applications. ...
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... Val-3 und Glu+11 von Aβ[144,165,469], wobei N -terminal verkürzte bzw. verlängerte Aβ -Peptide entstehen. ...
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... We speculate that these proteins interact with Aβ peptides soon after they start misfolding or accumulating, probably inside of the cells to circumvent the proteotoxicity. The presence of these and other intracellular proteins is at odds with extracellular amyloid deposition, but consistent with previous findings on the intracellular production of Aβ peptides [82][83][84]. It is also possible that these molecular chaperones were extracellularly exported through non-conventional secretory mechanisms [85]. ...
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... Since the secretases responsible for APP processing in humans are still not completely identified, the discovery of secretases in yeast may help in the identification of new human secretases by homology. Though a possible β-secretase-like enzymatic activity was also reported in yeast [42], this finding was not supported by other works. Overcoming the lack of β-secretase-like activity, a fragment derived from the APP cleaved by β-secretase (C99) was expressed in yeast [43]. ...
... Furthermore, the relationship of testosterone to the AD-specific pathologies of amyloid-beta and phospohorylated tau (p-Tau) has been studied in cellular and animal models. Testosterone treatment of cultured rat neurons reduced amyloid-beta precursor protein and soluble amyloid-beta secretion over time [35] and protected hippocampal neurons from amyloid-beta induced cell death [36]. In male rats with gonadectomies, testosterone treatment reversed amyloid-beta accumulation in the brain [37]. ...
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... Intranasal insulin administration has decreased Aβ levels in 3xTg-AD mice brains (Chen et al., 2014). The reduction in Aβ accumulation may be due to the observation that activating the insulin signaling pathway improves Aβ precursor protein transport and metabolism via the Erk/MAPK signaling pathway and the regulation of α, β, and γ secretases (Gasparini et al., 2001;Gasparini et al., 2002;Cai et al., 2015). Conversely, many human studies have reported that the insulin-activated signaling pathways increase Aβ secretion levels in the cerebrospinal fluid (Watson et al., 2003) but accelerate Aβ clearance in the brain and reduce plasma Aβ levels ( Figure 2A) (Reger et al., 2008a). ...
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... Interestingly, especially since the variant is located in the transmembrane region, p.(M476T) replaces a hydrophobic amino acid (methionine) with a polar amino acid with an uncharged side chain (threonine). The transmembrane domain is necessary for the access of BACE1 enzymatic activity to the cellular APP substrate [40]. Although mutations in the APP gene near the β-secretase sites can cause autosomal dominant AD [41][42][43], to date, no gene variations in the BACE1 gene have been directly linked to the disease. ...
... The γ-site ends at Aβ40 or Aβ42, and AICD starts at Aβ49 or Aβ50. This discrepancy with missing amino acid residues led to the new identification of the ε-cleavage site at Aβ49 [11][12][13][14] . The question of whether the γand ε-cleavages occur sequentially or independently from each other was answered by a new identification of the ζ-cleavage site at Aβ46 15,16 . ...
Reference: γ-Secretase in Alzheimer’s disease
