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...

Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.

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