A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease

Bush, Ashley I.; Multhaup, Gerhard; Moir, Robert D.; Williamson, Timothy G.; Small, David H.; Rumble, Baden; Pollwein, Peter; Beyreuther, Konrad; Masters, Colin L.

doi:10.1016/s0021-9258(19)85394-2

Cited by 275 publications

(64 citation statements)

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“…Wnt5 is a member of the large family of Wnt ligands, some of whose receptors and co-receptors harbor a conserved extracellular CRD thought to be important for Wnt binding ( Dann et al, 2001 ; Oishi et al, 2003 ). Intriguingly, APP harbors a CRD-like domain ( Bush et al, 1993 ) in its extracellular region that includes 12 cysteine residues conserved across APP paralogs and orthologs ( Figure 2A ). The distribution of the cysteine residues resembles those present in the CRDs of other PCP receptors such as Fz and Ror-2 ( Figure 2—figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

The amyloid precursor protein is a conserved Wnt receptor

Liu

Zhang

Nicolas

et al. 2021

eLife

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The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner.

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Section: Resultsmentioning

confidence: 99%

The amyloid precursor protein is a conserved Wnt receptor

Liu

Zhang

Nicolas

et al. 2021

eLife

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“…The large extracellular part of APP contains the copper-binding domain (CuBD) [141,144,283]. A Zn(II) site is located within residues 181−200 of APP [284]. In addition, several other Cu(II) and Zn(II) sites are present in the E2 domain of APP-like proteins [139,285].…”

Section: Biochemical Evidence: App/aβ and Copper Transportmentioning

confidence: 99%

Copper imbalance in Alzheimer’s disease: Convergence of the chemistry and the clinic

Kepp

Squitti

2019

Coordination Chemistry Reviews

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Content 1. Introduction 2. The amyloid hypothesis and its main problems 3. Brain copper homeostasis 4. The critical Kd of CuAD 5. Clinical evidence: Copper dyshomeostasis in AD 6. Biochemical evidence: APP/Aβ and copper transport 7. Molecular mechanisms of copper toxicity in CuAD 8. Analogies to other Cu-related diseases 9. Combining the facts into a simple model of AD due to copper dyshomeostasis 10. Conclusions

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“…2003). In addition, dimerization may also depend on Zn binding through a conserved region of amino acids between position 170 and 188 (Bush et al. 1993; Scheuermann et al.…”

Section: App Processing and Metalsmentioning

confidence: 99%

The role of metallobiology and amyloid‐β peptides in Alzheimer’s disease

Roberts

Ryan

Bush

et al. 2011

Journal of Neurochemistry

249

204

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J. Neurochem. (2012) 120 (Suppl. 1), 149–166. Abstract The biggest risk factor for Alzheimer’s disease is the process of ageing, but the mechanisms that lead to the manifestation of the disease remain to be elucidated. Why age triggers the disease is unclear but an emerging theme is the inability for a cell to efficiently maintain many key processes such as energy production, repair, and regenerative mechanisms. Metal ions are essential to the metabolic function of every cell. This review will explore the role and reported changes in metal ions in Alzheimer disease, particularly the brain, blood and cerebral spinal fluid, emphasizing how iron, copper and zinc may be involved through the interactions with amyloid precursor protein, the proteolytically cleaved peptide amyloid‐beta (Aβ), and other related metalloproteins. Finally, we explore the monomeric makeup of possible Aβ dimers, what a dimeric Aβ species from Alzheimer’s disease brain tissue is likely to be composed of, and discuss how metals may influence Aβ production and toxicity via a copper catalyzed dityrosine cross‐link.

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A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease

Cited by 275 publications

References 0 publications

The amyloid precursor protein is a conserved Wnt receptor

The amyloid precursor protein is a conserved Wnt receptor

Copper imbalance in Alzheimer’s disease: Convergence of the chemistry and the clinic

The role of metallobiology and amyloid‐β peptides in Alzheimer’s disease

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