Amyloid precursor protein 96–110 and β-amyloid 1–42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids

Abstract

Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96-110, play an important role in neurite Correspondence: Dr. T.A. Slotkin, Dept. of Pharmacology & Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710-3813, Tel (919) 681 8015, Fax (919) 684 8197, e-mail: t.slotkin@duke.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP 96-110 in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of β-amyloid 1-42 (Aβ42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer's Disease. Although both peptides elicited dysmorphogenesis, Aβ42 was far more potent; in addition, whereas Aβ42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP 96-110 effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or α-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer's Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, α-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain. NIH Public Access

Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: a pharmacological survey screen

“…Several families of neurotransmitter are known to participate in the early development (i.e. cleavage and gastrulation) of invertebrates such as the sea urchin Buznikov et al 2008) and Drosophila (Colas et al 1999a,b). In vertebrates, several developmental roles for serotonin have been outlined, most notably craniofacial development (Reisoli et al 2010) and patterning of the left-right axis (Fukumoto et al 2005a,b;Carneiro et al 2011;Beyer et al 2012;Vandenberg et al 2012Vandenberg et al , 2014.…”

“…In addition, lipophilic analogs of serotonin, acetylcholine and cannabinoids have been shown to rescue sea urchin embryos from developmental defects induced by the amyloid protein fragments responsible for Alzheimer's disease (Buznikov et al. ).…”

“…In the sea urchin embryo, cleavage and gastrulation are, in part, regulated by serotonin ); a similar role was found for serotonin in the fruit fly model (Colas et al 1999a,b). In addition, lipophilic analogs of serotonin, acetylcholine and cannabinoids have been shown to rescue sea urchin embryos from developmental defects induced by the amyloid protein fragments responsible for Alzheimer's disease (Buznikov et al 2008).…”

The Sea Urchin Embryo: A Model for Studying Molecular Mechanisms Involved in Human Diseases and for Testing Bioactive Compounds

“…With respect to Aβ 42 , APP 96-110 had a weaker effect in disrupting development, requiring higher concentrations to produce the same malformations caused by Aβ 42 . APP 96-110 was dangerous only within a defined window of vulnerability corresponding about to the mid-blastula stage, whereas Aβ 42 had adverse effects from early cleavage to the pluteus stage [39]. For both peptides, developmental anomalies were prevented or reduced by the addition of neurotransmitters.…”

“…By using S. granularis, the effect of a specific 15-amino acid sequence (NWCKRGRKQCKTHPH) placed in positions 96-100 within the extracellular domain of the APP protein (APP 96-110 ) was evaluated and compared to that of Aβ 42 [39]. This fragment corresponds to a proteoglycanbinding domain that specifically controls neurite outgrowth and other aspects of neurodevelopment [40].…”