Amyloid-β Binds to the Extracellular Cysteine-rich Domain of Frizzled and Inhibits Wnt/β-Catenin Signaling

Abstract

The amyloid-␤ peptide (A␤) plays a major role in neuronal dysfunction and neurotoxicity in Alzheimer disease. However, the signal transduction mechanisms involved in A␤-induced neuronal dysfunction remain to be fully elucidated. A major current unknown is the identity of the protein receptor(s) involved in neuronal A␤ binding. Using phage display of peptide libraries, we have identified a number of peptides that bind A␤ and are homologous to neuronal receptors putatively involved in A␤ interactions. We report here on a cysteine-linked cyclic heptapeptide (denominated cSP5) that binds A␤ with high affinity and is homologous to the extracellular cysteine-rich domain of several members of the Frizzled (Fz) family of Wnt receptors. Based on this homology, we investigated the interaction between A␤ and Fz. The results show that A␤ binds to the Fz cysteine-rich domain at or in close proximity to the Wnt-binding site and inhibits the canonical Wnt signaling pathway. Interestingly, the cSP5 peptide completely blocks A␤ binding to Fz and prevents inhibition of Wnt signaling. These results indicate that the A␤-binding site in Fz is homologous to cSP5 and that this is a relevant target for A␤-instigated neurotoxicity. Furthermore, they suggest that blocking the interaction of A␤ with Fz might lead to novel therapeutic approaches to prevent neuronal dysfunction in Alzheimer disease. Alzheimer disease (AD)2 is a progressive neurodegenerative disorder characterized, in its early stages, by a striking inability to form new memories. Recent work indicates that cognitive and memory impairments in early AD are caused by synaptic dysfunction instigated by pathological assemblies of the amyloid-␤ peptide (A␤) (for recent reviews, see Refs. 1-3). Neuropathological hallmarks of AD include increased brain levels and extracellular build-up of A␤ aggregates, intraneuronal neurofibrillary tangles composed of hyperphosphorylated Tau, and, notably, synaptic loss (1). Despite the fact that A␤ has been strongly implicated in neuronal dysfunction and neurotoxicity in AD, the signal transduction mechanisms involved in the neuronal impact of A␤ remain to be fully elucidated. A major current unknown is the identity of the neuronal receptor(s) that bind A␤ and mediate neuronal dysfunction. Identification of such receptor(s) would provide considerable insight into mechanisms of pathogenesis and might reveal novel opportunities for the development of strategies to combat AD.The Wnt signaling pathway has been recently proposed to play a role in AD (for a review, see Ref. 4). Wnts are secreted glycoproteins that bind to and signal through Frizzled (Fz) receptors and mediate cell-cell communication (5). Wnt signaling regulates a variety of biological processes, including development, cell movement, polarity, axon guidance, and synapse formation (6). Different types of Wnt⅐Fz complexes may signal through the so-called canonical or noncanonical Wnt pathways. Canonical Wnt/Fz signaling results in stabilization and increased intracellular levels of ␤-cate...

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…Wnt signaling regulates a variety of critical biological processes, including development, cell movement, cell polarity, axon guidance, and synapse formation [50]. Magdesian and colleagues concluded that A␤ oligomers bind to Fz receptors, producing the inhibition of Wnt signaling, which causes tau phosphorylation and neurofibrillary tangles; that suggests a Wnt/␤-catenin toxicity pathway [48].…”

“…Magdesian et al showed that A␤ oligomers bind to the Frizzled (Fz) cysteine-rich domain at or in close proximity to the Wnt-binding site and inhibit the canonical Wnt signaling pathway [48]. Wnts are secreted glycoproteins that bind to and signal through Fz receptors and mediate cell-cell communication [49].…”

Alzheimer's Disease Affects Progenitor Cells through Aberrant β-Catenin Signaling

“…But previous studies have shown that A␤ can bind to several members of the frizzled receptor family, acting as an antagonist of Wnts (Magdesian et al, 2008), and that A␤ can lead to upregulation of the Wnt/␤-catenin signaling inhibitor Dickkopf1 (Krupnik et al, 1999). Such interference at the level of the frizzled receptor and the subsequent reduction of the downstream effector ␤-catenin could lead to downregulation of proneural bHLH factors, which are direct targets of Wnt/␤-catenin signaling during cortical development (Hirabayashi et al, 2004).…”

Investigating Amyloid β toxicity in Drosophila melanogaste

“…Additionally, Aβ interacts with the α7 nicotinic acetylcholine receptor, promoting the internalization of receptors and the accumulation of intracellular Aβ [147]. Studies have also showed that Aβ interaction to the Frizzled (Fz) receptor inhibit Wnt signaling, resulting in downstream processes causing tau phosphorylation and formation of NFTs [148]. These are a few examples of Aβ interactions with receptors, and the sometimes contradictory reports regarding Aβ interactions might be because different Aβ assemblies or conformations have different targets.…”