Amyloid-β precursor protein mediates neuronal toxicity of amyloid β through Go protein activation

Vigo, Francisco Solá; Kedikian, Gabriela; Heredia, Lorena; Heredia, Florencia; Añel, Alberto Díaz; Rosa, Alberto L.; Lorenzo, Alfredo

doi:10.1016/j.neurobiolaging.2007.11.017

Cited by 39 publications

(61 citation statements)

References 51 publications

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“…Furthermore, the G␣ o subunit has been shown to be involved in Alzheimer's disease, in which the amyloid precursor protein mediates the neuronal toxicity of A␤ oligomers through G␣ o activation (67). It would be interesting to evaluate how these elements interact and how FZD9 is involved in these processes.…”

Section: Discussionmentioning

confidence: 99%

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Ramirez

Ramos-Fernández

Henríquez

et al. 2016

Journal of Biological Chemistry

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Wnt ligands play crucial roles in the development and regulation of synapse structure and function. Specifically, Wnt-5a acts as a secreted growth factor that regulates dendritic spine formation in rodent hippocampal neurons, resulting in postsynaptic development that promotes the clustering of the PSD-95 (postsynaptic density protein 95). Here, we focused on the early events occurring after the interaction between Wnt-5a and its Frizzled receptor at the neuronal cell surface. Additionally, we studied the role of heterotrimeric G proteins in Wnt-5a-dependent synaptic development. We report that FZD9 (Frizzled9), a Wnt receptor related to Williams syndrome, is localized in the postsynaptic region, where it interacts with Wnt-5a. Functionally, FZD9 is required for the Wnt-5a-mediated increase in dendritic spine density. FZD9 forms a precoupled complex with G␣ o under basal conditions that dissociates after Wnt-5a stimulation. Accordingly, we found that G protein inhibition abrogates the Wnt-5a-dependent pathway in hippocampal neurons. In particular, the activation of G␣ o appears to be a key factor controlling the Wnt-5a-induced dendritic spine density. In addition, we found that G␤␥ is required for the Wnt-5a-mediated increase in cytosolic calcium levels and spinogenesis. Our findings reveal that FZD9 and heterotrimeric G proteins regulate Wnt-5a signaling and dendritic spines in cultured hippocampal neurons.The Wnt family proteins are secreted growth factors that regulate developmental processes, such as cell fate and polarity and general cell maintenance events, by modulating homeostasis and the cell cycle (1, 2). Furthermore, Wnt signaling controls various steps in the differentiation of the central nervous system (3-5), including axon guidance, dendrite development, synapse formation and plasticity (6, 7). Certain Wnt ligands, such as Wnt-7a and Wnt-3a, regulate the development and activity of the pre-and postsynaptic regions of glutamatergic synapses (8 -10). Similarly, previous results have shown that Wnt-5a regulates the synaptic structure and function by inducing the clustering of PSD-95 through the activation of the c-Jun N-terminal kinase (JNK) (11) and modulates glutamate receptors through nitric oxide production (12). Additionally, Wnt-5a promotes the de novo formation of dendritic spines in hippocampal neurons (13) through the non-canonical Wnt/Ca 2ϩ pathway.The Frizzled (FZD) 2 family has 10 members in vertebrates and represents unconventional G protein-coupled receptors (GPCRs) (14). FZD proteins have been identified as Wnt receptors, and they can mediate the signaling triggered by several Wnt ligands. Wnt-5a activity has been linked to several FZDs receptors and other co-receptors in different model systems (15-18). However, the FZD receptor mediating Wnt-5a signaling and spine formation in hippocampal neurons has not yet been identified.Several signaling cascades can be triggered upon Wnt binding to a FZD receptor, including canonical (i.e. ␤-catenin-dependent) and non-canonical pathways (19). Co...

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Section: Discussionmentioning

confidence: 99%

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Ramirez

Ramos-Fernández

Henríquez

et al. 2016

Journal of Biological Chemistry

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“…sAPP has been reported to have many neuroprotective and neurotrophic functions within the central nervous system (CNS) (Mattson et al, 1993); for instance, sAPP administration reduced neuronal injury and improved functional outcome following rat TBI (Thornton et al, 2006). The -secretase pathway is a non-amyloidogenic pathway in which the majority of APP is normally processed (Suh and Checler 2002), while after brain injury the -and -secretase pathways are activated and are responsible for producing the toxic sAPP (Matrone et al, 2008;Sola Vigo et al, 2008) and A (Mills and www.intechopen.com Reiner 1999; Stone et al, 2002;Blasko et al, 2004). For instance, sAPP was shown to induce apoptotic cell death in PC 12 cells and neuronal degeneration in rat hippocampal neurons (Matrone et al, 2008;Sola Vigo et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The -secretase pathway is a non-amyloidogenic pathway in which the majority of APP is normally processed (Suh and Checler 2002), while after brain injury the -and -secretase pathways are activated and are responsible for producing the toxic sAPP (Matrone et al, 2008;Sola Vigo et al, 2008) and A (Mills and www.intechopen.com Reiner 1999; Stone et al, 2002;Blasko et al, 2004). For instance, sAPP was shown to induce apoptotic cell death in PC 12 cells and neuronal degeneration in rat hippocampal neurons (Matrone et al, 2008;Sola Vigo et al, 2008). Nakagawa et al reported that the APP overexpression of ST6Gal-1 in Neuro2 enhanced producing sAPP and the level of the extracellular sAPP form is increased the level of sAPP form (Nakagawa et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Expression and Cerebral Function of Amyloid Precursor Protein After Rat Traumatic Brain Injury

Itoh¹,

Imano²,

Nishida³

et al. 2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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“…A␤ can induce APP oligomerization and caspase cleavage at Asp 664 , liberating an APP fragment containing the C-terminal 31 amino acids (52,53). This APP C-terminal fragment is neurotoxic when overexpressed (54) and may activate a G-protein signaling cascade (55).…”

Section: A␤-app Interactions and Toxicitymentioning

confidence: 99%

Amyloid β-Protein Toxicity and the Pathogenesis of Alzheimer Disease

Yankner

2009

Journal of Biological Chemistry

197

166

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Although amyloid deposition was noted by Alzheimer in 1907 (1), it has been only 17 years since the toxicity of A␤ 2 was first described (2). The prevailing view through most of the twentieth century was that A␤ is a marker of disease progression in AD but does not play a role in the neurodegenerative process. This view changed in the 1990s with the articulation of the amyloid hypothesis, which posits that abnormal accumulation of A␤ in the brain is a direct cause of neurodegeneration and cognitive decline in AD. The hypothesis is supported by the identification of mutations in APP (3) and presenilins 1 and 2 (4 -7) that increase A␤ generation or, more importantly, the generation of a minor 42-amino acid form (A␤42) with an increased propensity for aggregation (8). This review sets forth the major lines of evidence for A␤ toxicity and focuses on the interface between A␤ toxicity and molecular mechanisms of synaptic plasticity. Do Plaques Matter?The early studies of Blessed and co-workers (9) suggested that plaque numbers were directly related to quantitative measures of cognitive decline in the aged population. However, subsequent studies carried out by Terry et al. (10) cast doubt on the predictive value of plaque numbers, suggesting instead that NFTs and synapse loss were more reliable predictors of cognitive decline. Moreover, plaque formation is a common feature of the aging human brain that can occur in the absence of cognitive decline (11). More recently, it has been suggested that accumulation of toxic oligomers of A␤ may be more relevant than plaques to mechanisms involved in cognitive decline.Transgenic mouse models expressing APP and presenilin variants associated with FAD have provided important insights into structural, neurophysiological, and behavioral effects of A␤ accumulation in the brain (12). Multiphoton imaging studies have demonstrated disrupted neurites and decreased spine density in association with fibrillar A␤ deposits in the Tg2576 transgenic mouse model that expresses the APPsw mutation (13,14). In addition, stereologic mapping of neuronal cell density showed some degree of neuronal loss in the immediate vicinity of A␤ deposits (15). The neuritic dystrophy observed in APP transgenic mice appears to be directly related to the fibrillar component of A␤ deposits. When the APP transgenic was placed on an apoE-deficient background, A␤ deposition still occurred, but fibrillar deposits were absent, and neuritic dystrophy was markedly reduced. When apoE3 or apoE4 was expressed, fibrillar A␤ deposits appeared with concomitant neuritic degeneration that was greater for apoE4 than for apoE3 (16,17). However, it was unclear from these studies which came first, neuritic degeneration or deposition of fibrillar A␤. Another study suggested that axonal dystrophy and altered axonal transport occur early in AD and may lead to amyloid deposition (18). The question of which comes first, amyloid or neuritic dystrophy, was recently addressed by in vivo multiphoton microscopy in an APPswe/PS1d9XYFP transgeni...

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Amyloid-β precursor protein mediates neuronal toxicity of amyloid β through Go protein activation

Cited by 39 publications

References 51 publications

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Expression and Cerebral Function of Amyloid Precursor Protein After Rat Traumatic Brain Injury

Amyloid β-Protein Toxicity and the Pathogenesis of Alzheimer Disease

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