Distinct in vivo role of APPsα versus APPsβ for spine density, synaptic plasticity and cognition

Richter, Max

doi:10.26226/morressier.5b31ec642afeeb001345abe6

Cited by 12 publications

(32 citation statements)

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“…Despite many studies, the cell surface receptor(s) which transduce the sAPPα signal are yet to be conclusively identified, though specific candidates have emerged (Rice et al, 2017, 2019; Richter et al, 2018; Mockett et al, 2019). Here, we pharmacologically inhibited likely candidates mediating sAPPα’s plasticity-promoting effects and observed the effect on sAPPα-induced Arc protein levels (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

“…A crucial, yet outstanding question in the literature is the identity of the ‘sAPPα receptor.’ Previous evidence has described a role of GABA B (Rice et al, 2017, 2019), Na/K ATP’ase (Dorard et al, 2018), α7nAch (Richter et al, 2018) and NMDA receptors (Gakhar-Koppole et al, 2008; Mockett et al, 2019) in mediating sAPPα’s plasticity enhancing effects. To understand the receptors contributing to the facilitated Arc expression, we investigated the possible contributions of these and other candidate receptors (mGluRI/II and TrkB) due to their similar neuromodulatory or plasticity-promoting properties (Raymond et al, 2000; Mockett et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, while the receptor/s mediating the actions of sAPPα have not been conclusively identified, candidate receptors and downstream pathways overlap with those identified in relation to the regulation of Arc. Somatodendritic translation of Arc mRNA is dependent on Ca 2+ signaling via ionotropic receptors, including the N -methyl-d-aspartate receptor (NMDA; Chen et al, 2017) and α7 nicotinic acetylcholine receptor (α7nAchR; Kristensen et al, 2007); these receptors are both candidates for mediating sAPPα’s actions (Taylor et al, 2008; Richter et al, 2018; Mockett et al, 2019). Furthermore, downstream signaling molecules such as protein kinase G (PKG), mitogen activated protein kinase (MAPK) and CaMKII have not only been shown to enhance Arc mRNA or regulate Arc protein expression (Huang et al, 2007; Gakhar-Koppole et al, 2008; Ota et al, 2010; Chasseigneaux et al, 2011), but also mediates the neuroprotective, neurotrophic and plasticity-enhancing effects of sAPPα (Furukawa et al, 1996a; Claasen et al, 2009; Mockett et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Secreted Amyloid Precursor Protein-Alpha Promotes Arc Protein Synthesis in Hippocampal Neurons

Livingstone

Elder

Barrett

et al. 2019

Front. Mol. Neurosci.

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Secreted amyloid precursor protein-α (sAPPα) is a neuroprotective and memory-enhancing molecule, however, the mechanisms through which sAPPα promotes these effects are not well understood. Recently, we have shown that sAPPα enhances cell-surface expression of glutamate receptors. Activity-related cytoskeletal-associated protein Arc (Arg3.1) is an immediate early gene capable of modulating long-term potentiation, long-term depression and homeostatic plasticity through regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor localization. Accordingly, we hypothesized that sAPPα may enhance synaptic plasticity, in part, by the de novo synthesis of Arc. Using primary cortical and hippocampal neuronal cultures we found that sAPPα (1 nM, 2 h) enhances levels of Arc mRNA and protein. Arc protein levels were increased in both the neuronal somata and dendrites in a Ca 2+ /calmodulin-dependent protein kinase II-dependent manner. Additionally, dendritic Arc expression was dependent upon activation of mitogen-activated protein kinase and protein kinase G. The enhancement of dendritic Arc protein was significantly reduced by antagonism of N -methyl- D -aspartate (NMDA) and nicotinic acetylcholine (α7nACh) receptors, and fully eliminated by dual application of these antagonists. This effect was further corroborated in area CA1 of acute hippocampal slices. These data suggest sAPPα-regulated plasticity within hippocampal neurons is mediated by cooperation of NMDA and α7nACh receptors to engage a cascade of signal transduction molecules to enhance the transcription and translation of Arc.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Secreted Amyloid Precursor Protein-Alpha Promotes Arc Protein Synthesis in Hippocampal Neurons

Livingstone

Elder

Barrett

et al. 2019

Front. Mol. Neurosci.

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“…This possibly also affects sAPP function, which has been attributed at least partly to a short stretch consisting of 16 residues between the α‐ and β‐cleavage sites (Richter et al . ). As the presence of this short stretch appears to alter the conformation of sAPPα in a critical way (Peters‐Libeu et al .…”

Section: Discussionmentioning

confidence: 97%

Copper and zinc ions govern the trans‐directed dimerization of APP family members in multiple ways

August

Schmidt

Klingler

et al. 2019

Journal of Neurochemistry

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The amyloid precursor protein (APP) and its homologs amyloid precursor‐like protein 1 (APLP1) and APLP2 have central physiological functions in transcellular adhesion that depend on copper and zinc mediated trans‐directed dimerization of the extracellular domains E1 and E2. Copper binds to three distinct sites in APP, one in the copper binding (CuBD) and growth factor‐like (GFLD) domains each within E1, and one in the E2 domain. For APLP1 and APLP2, metal binding has so far only been shown for the E2 domain. Zinc binding has been reported for all APP family members to a unique site in the E2 domain and an additional site essential for APLP1 E2 domain trans‐dimerization. Using isothermal titration calorimetry, co‐immunoprecipitation, and in vitro bead aggregation assays, we show that copper promotes cis‐ as well as trans‐directed dimerization of APLP1 and APLP2, similar as reported previously for APP. Furthermore, we report a APP‐specific zinc binding site with nanomolar affinity located in the E1 domain, whereas no binding of zinc to the individual subdomains GFLD or CuBD was detected. Zinc binding did not affect the cis‐ but trans‐dimerization of APP and APLP1. Furthermore, zinc binding inhibited copper‐induced trans‐directed dimerization of APP. Together, we identified a high‐affinity APP‐specific zinc binding site in the E1 domain and revealed contrasting cis‐ and trans‐directed dimerization properties of APP, APLP1, and APLP2 in dependence on zinc and copper ions. Consequently, changes in metal ion homeostasis, as reported in the context of synaptic activity and neurodegenerative diseases, appear as key modulators of homo‐ and heterotypic trans‐cellular APP/APLPs complexes.

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“…Ulrike Müller, a professor at the Institute of Pharmacy and Molecular Biotechnology at the University of Heidelberg in Germany, and her colleagues, including Korte, have found that overexpressing sAPPalpha in the brains of a mouse model of Alzheimer's disease mitigated neuronal defects and improved memory (9). More recently, Müller's group has shown that sAPPalpha may operate through a specific acetylcholine receptor to affect synaptic function, plasticity, and memory in mice (10). "It's beneficial, it's good for the brain," says Müller.…”

Section: Intracellular Fragments Can Affect Gene Expression To Promotmentioning

confidence: 99%

Family of protein fragments promises fresh view of Alzheimer's disease

Schubert¹

2019

Proc. Natl. Acad. Sci. U.S.A.

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Distinct in vivo role of APPsα versus APPsβ for spine density, synaptic plasticity and cognition

Cited by 12 publications

References 0 publications

Secreted Amyloid Precursor Protein-Alpha Promotes Arc Protein Synthesis in Hippocampal Neurons

Secreted Amyloid Precursor Protein-Alpha Promotes Arc Protein Synthesis in Hippocampal Neurons

Copper and zinc ions govern the trans‐directed dimerization of APP family members in multiple ways

Family of protein fragments promises fresh view of Alzheimer's disease

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