Copper brain homeostasis: Role of amyloid precursor protein and prion protein

Inestrosa, Nibaldo C.; Cerpa, Waldo; Varela-Nallar, Lorena

doi:10.1080/15216540500264620

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…In addition, in the absence of APLP2, copper accumulation increases in a gene dose-dependant manner with decreasing APP expression in APP-APLP2 double KO mice [84] . Altogether these KO studies provide strong evidence that APP may participate in the modulation of brain copper homeostasis and oxidative damage (reviewed by Inestrosa et al [85] ). Defects in the neuroprotective function of APP may reflect a disturbed copper ion homeostasis which has been shown to occur in the brain of AD patients (reviewed by Bayer and Multhaup [86] and Cerpa et al [87] ).…”

Section: App Plays a Role In Brain Repair And Oxidativementioning

confidence: 99%

Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

2006

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The amyloid precursor protein (APP) is a widely expressed transmembrane protein that is cleaved to generate Aβ peptides in the central nervous system and is a key player in the pathogenesis of Alzheimer’s disease. The precise biological functions of APP still remain unclear although various roles have been proposed. While a commonly accepted model argues that Aβ peptides are the cause of onset and early pathogenesis of Alzheimer’s disease, recent discussions challenge this ‘Aβ hypothesis’ and suggest a direct role for APP in this neurodegenerative disease. Loss-of-function studies are an efficient way to elucidate the role of proteins and concurrently a variety of in vitro and in vivo studies has been performed for APP where protein levels have been downregulated and functional consequences monitored. Complete disruption of APP gene expression has been achieved by the generation of APP knockout animal models. Further knockdown studies using antisense and RNA interference have allowed scientists to reduce APP expression levels and have opened new avenues to explore the physiological roles of APP. In the present review, we focus on knockout and knockdown approaches that have provided insights into the physiological functions of APP and discuss their advantages and drawbacks.

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Section: App Plays a Role In Brain Repair And Oxidativementioning

confidence: 99%

Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

2006

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“…of PrP C is unknown, but recent investigations focus on the ability of the octarepeat domain to take up copper (5,(7)(8)(9)(10)(11). PrP C protects against apoptosis (12) and radical-mediated oxidative damage (13,14) and even stimulates nerve cell growth and development (15).…”

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confidence: 99%

The Affinity of Copper Binding to the Prion Protein Octarepeat Domain: Evidence for Negative Cooperativity

2006

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The prion protein (PrP) binds Cu 2+ in its N-terminal octarepeat domain, composed of four or more tandem PHGGGWGQ segments. Previous work from our laboratory demonstrates that copper interacts with the octarepeat domain through three distinct coordination modes at pH 7.4, depending upon the precise ratio of Cu 2+ to protein. Here, we apply both electron paramagnetic resonance (EPR) and fluorescence quenching to determine the copper affinity for each of these modes. At low copper occupancy, which favors multiple His coordination, the octarepeat domain binds Cu 2+ with a dissociation constant of 0.10 (±0.08) nM. In contrast, high copper occupancy, involving coordination through deprotonated amide nitrogens, exhibits a weaker affinity characterized by dissociation constants in the range of 7.0-12.0 μM. Decomposition of the EPR spectra reveals the proportions of all coordination species throughout the copper concentration range and identifies significant populations of intermediates, consistent with negative cooperativity. At most copper concentrations, the Hill coefficient is less than 1.0 and approximately 0.7 at half copper occupancy. These findings demonstrate that the octarepeat domain is responsive to a remarkably wide copper concentration range covering approximately 5 orders of magnitude. Consideration of these findings, along with the demonstrated ability of the protein to quench copper redox activity at high occupancy, suggests that PrP may function to protect cells by scavenging excess copper.The prion protein (PrP) 1 is responsible for a novel class of infectious, neurodegenerative diseases collectively known as the transmissible spongiform encephalopathies (TSEs) (1-3). The TSEs include scrapie in sheep, mad cow disease (bovine spongiform encephalopathy, BSE), chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans. The normal cellular form of the prion protein, referred to as PrP C , is found in a wide range of tissues of all mammalian and avian species. A misfolding event converts the protein to the infectious, β-sheet-rich scrapie form (PrP Sc ) responsible for the TSEs.PrP C is a GPI-anchored glycoprotein expressed in abundance on the surface of neurons, predominantly on presynaptic membranes (4,5). The mature form of PrP, consisting of residues 23-231 in hamster, has a globular C-terminal domain and a largely unstructured N-terminal domain (6) (Figure 1). The C-terminal domain (residues 125-231) contains three α helices, two of which are stabilized by a single interhelical disulfide bond, and a small antiparallel β sheet. The flexible N-terminal domain is glycine-rich and highly flexible. Within the flexible N-terminal region of PrP is the octarepeat domain, composed of four or five highly conserved, contiguous repeats of the eight-residue sequence PHGGGWGQ. The physiological function

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“…Although the precise biological roles of APP are elusive, studies of over-and under-expression of APP suggest a number of important physiological functions [1,2]. Such functions include neurite outgrowth, synaptogenesis, neurogenesis [3], cell adhesion and migration, axonal transport [4], brain copper homeostasis [5], and brain and somatic development through Notch and Fe65 signaling pathway [6,7]. Because APP seems to have important roles in neuronal plasticity and synaptic functions, it has been hypothesized that alterations in physiological functions of APP may be the primary events leading to AD [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Aβ1‐6 upregulates IL‐10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease

Kim

Tahara

Maxwell

et al. 2007

The Journal of Gene Medicine

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Background-One of the pathological hallmarks of Alzheimer disease (AD) is deposits of amyloid β-peptide (Aβ) in neuritic plaques and cerebral vessels. Immunization of AD mouse models with Aβ reduces Aβ deposits and improves memory and learning deficits. Because recent clinical trials of immunization with Aβ were halted due to brain inflammation that was presumably induced by a T cell-mediated autoimmune response, vaccination modalities that elicit predominantly humoral immune responses are currently being developed.Methods-We have nasally immunized young AD mouse model with an adenovirus vector encoding 11 tandem repeats of Aβ1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A (PEDI), AdPEDI-(Aβ1-6) 11 , in order to evaluate the efficacy of the vector in preventing Aβ deposits in the brain. We also have investigated immune responses of mice to AdPEDI-(Aβ1-6) 11 .Results-Nasal immunization of an AD mouse model with AdPEDI-(Aβ1-6) 11 elicited a predominant IgG1 response and reduced Aβ load in the brain. The plasma IL-10 level in the AD mouse model was upregulated after immunization and, upon the stimulation with PEDI-(Aβ1-6) 11 , marked IL-10 responses were found in splenic CD4 + T cells from C57BL/6 mice that had been immunized with AdPEDI-(Aβ1-6) 11 .Conclusions-These results suggest that the induction of Th2-biased responses with AdPEDI-(Aβ1-6) 11 in mice is mediated in part through the upregulation of IL-10, which inhibits activation of dendritic cells that dictate the induction of Th1 cells.

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Copper brain homeostasis: Role of amyloid precursor protein and prion protein

Cited by 21 publications

References 40 publications

Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

The Affinity of Copper Binding to the Prion Protein Octarepeat Domain: Evidence for Negative Cooperativity

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Aβ1‐6 upregulates IL‐10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease

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