CoChat
Sign Up
Cited by 374Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 254 of the 254 references it cites were found in a registry or an index.

Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease

Open access
Ferreira, Sergio T., Lourenco, Mychael V., Oliveira, Mauricio M., De Felice, Fernanda G.·2015·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2015.00191PMC PMC4443025
Open this paper in CoChat — free accountOpen PDF

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-β peptide (Aβ) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Aβ leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Aβ oligomers (AβOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Aβ oligomer hypothesis for Alzheimer's pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fncel.2015.00191

Cites

254 of 254 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Synapse under siege. A simplified scheme illustrating some of the mechanisms by which AβOs (AβOs; represented as red asterisks) impact synapse plasticity and function. At the pre-synaptic terminal, AβOs inhibit microtubule-based fast axonal transport (FAT) in a tau-independent manner (Decker et al., 2010b; Ramser et al., 2013; Gan and Silverman, 2015; Takach et al., 2015), resulting in reduced or interrupted transport of various cargoes, including brain-derived neurotrophic factor (BDNF), to synapses. FAT inhibition may involve physical or functional interaction of AβOs with axonal voltage-gated calcium channels (VGCC), calcium influx into the axon and activation of calcineurin (CaN). Deregulated calcium levels also triggers increased pre-synaptic glutamate release (Brito-Moreira et al., 2011). Release of the NMDA receptor (NMDAR) co-agonist, D-serine, is also increased in neurons exposed to AβOs (Brito-Moreira et al., 2011; Madeira et al., 2015), resulting in elevated basal excitatory tonus. At the dendritic spine, AβOs aberrantly activate NMDARs, triggering increased calcium influx and increased production of reactive oxygen species (ROS; De Felice et al., 2007; Decker et al., 2010a; Saraiva et al., 2010; Paula-Lima et al., 2011), likely mediated by mitochondrial dysfunction. NMDAR-mediated calcium influx causes ryanodyne receptor-mediated calcium release from endoplasmic reticulum (ER) stores (Paula-Lima et al., 2011). Elevated calcium levels at the spine activate CaN to dephosphorylate NMDARs and AMPARs at specific phosphoepitopes, causing their removal from synapses and internalization (Snyder et al., 2005; Hsieh et al., 2006; Jürgensen et al., 2011). CaN activation has also been implicated in Aβ-induced spine loss (Wu et al., 2010; not represented in the scheme for simplicity). Calcium-dependent activation of calcium/calmodulin-dependent kinase II (CaMKII) and casein kinase II (CKII) also appears to mediate removal of NMDARs from synapses (De Felice et al., 2009; not represented in the current scheme). AβOs block insulin signaling by instigating removal of insulin receptors (IRs) from the neuronal plasma membrane (De Felice et al., 2009; not represented here), inhibiting IR autophosphorylation (Zhao et al., 2008; not represented), and by inhibiting IR-mediated tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1; Bomfim et al., 2012; not represented). AβOs instigate brain microgliosis and increased microglial production/secretion of TNF-α (Ledo et al., 2013; unpublished results). Aberrant TNF-α signaling activates cell stress kinases (c-Jun N-terminal kinase, JNK; IκB kinase, IKK; double-stranded DNA-dependent protein kinase, PKR; Bomfim et al., 2012; Lourenco et al., 2013), resulting in serine phosphorylation and further inhibition of IRS-1. PKR also phosphorylates eukaryotic initiation factor 2 α (eIF2α; Lourenco et al., 2013). eIF2α is further phosphorylated by PKR-related ER resident kinase (PERK), a kinase that executes one of the three branches of the unfolded protein response (UPR) that is activated by ER stress in neurons exposed to AβOs (Lourenco et al., 2013; Ma et al., 2013). Insulin signaling inhibition and eIF2α-P lead to blockade of protein synthesis, essential for synaptic plasticity (Buffington et al., 2014). Additional mechanisms (not included here) thought to further contribute to synapse failure include deregulation of the actin cytoskeleton at spines (Lacor et al., 2004; Davis et al., 2011), loss of pre- and post-synaptic proteins (e.g., synaptophysin, PSD-95; Roselli et al., 2005; Sebollela et al., 2012; Figueiredo et al., 2013), Fyn kinase-mediated surface removal of NMDARs and spine loss (Um et al., 2012), among others.
Figure 1 Synapse under siege. A simplified scheme illustrating some of the mechanisms by which AβOs (AβOs; represented as red asterisks) impact synapse plasticity and function. At the pre-synaptic terminal, AβOs inhibit microtubule-based fast axonal transport (FAT) in a tau-independent manner (Decker et al., 2010b; Ramser et al., 2013; Gan and Silverman, 2015; Takach et al., 2015), resulting in reduced or interrupted transport of various cargoes, including brain-derived neurotrophic factor (BDNF), to synapses. FAT inhibition may involve physical or functional interaction of AβOs with axonal voltage-gated calcium channels (VGCC), calcium influx into the axon and activation of calcineurin (CaN). Deregulated calcium levels also triggers increased pre-synaptic glutamate release (Brito-Moreira et al., 2011). Release of the NMDA receptor (NMDAR) co-agonist, D-serine, is also increased in neurons exposed to AβOs (Brito-Moreira et al., 2011; Madeira et al., 2015), resulting in elevated basal excitatory tonus. At the dendritic spine, AβOs aberrantly activate NMDARs, triggering increased calcium influx and increased production of reactive oxygen species (ROS; De Felice et al., 2007; Decker et al., 2010a; Saraiva et al., 2010; Paula-Lima et al., 2011), likely mediated by mitochondrial dysfunction. NMDAR-mediated calcium influx causes ryanodyne receptor-mediated calcium release from endoplasmic reticulum (ER) stores (Paula-Lima et al., 2011). Elevated calcium levels at the spine activate CaN to dephosphorylate NMDARs and AMPARs at specific phosphoepitopes, causing their removal from synapses and internalization (Snyder et al., 2005; Hsieh et al., 2006; Jürgensen et al., 2011). CaN activation has also been implicated in Aβ-induced spine loss (Wu et al., 2010; not represented in the scheme for simplicity). Calcium-dependent activation of calcium/calmodulin-dependent kinase II (CaMKII) and casein kinase II (CKII) also appears to mediate removal of NMDARs from synapses (De Felice et al., 2009; not represented in the current scheme). AβOs block insulin signaling by instigating removal of insulin receptors (IRs) from the neuronal plasma membrane (De Felice et al., 2009; not represented here), inhibiting IR autophosphorylation (Zhao et al., 2008; not represented), and by inhibiting IR-mediated tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1; Bomfim et al., 2012; not represented). AβOs instigate brain microgliosis and increased microglial production/secretion of TNF-α (Ledo et al., 2013; unpublished results). Aberrant TNF-α signaling activates cell stress kinases (c-Jun N-terminal kinase, JNK; IκB kinase, IKK; double-stranded DNA-dependent protein kinase, PKR; Bomfim et al., 2012; Lourenco et al., 2013), resulting in serine phosphorylation and further inhibition of IRS-1. PKR also phosphorylates eukaryotic initiation factor 2 α (eIF2α; Lourenco et al., 2013). eIF2α is further phosphorylated by PKR-related ER resident kinase (PERK), a kinase that executes one of the three branches of the unfolded protein response (UPR) that is activated by ER stress in neurons exposed to AβOs (Lourenco et al., 2013; Ma et al., 2013). Insulin signaling inhibition and eIF2α-P lead to blockade of protein synthesis, essential for synaptic plasticity (Buffington et al., 2014). Additional mechanisms (not included here) thought to further contribute to synapse failure include deregulation of the actin cytoskeleton at spines (Lacor et al., 2004; Davis et al., 2011), loss of pre- and post-synaptic proteins (e.g., synaptophysin, PSD-95; Roselli et al., 2005; Sebollela et al., 2012; Figueiredo et al., 2013), Fyn kinase-mediated surface removal of NMDARs and spine loss (Um et al., 2012), among others.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

2 retracted

Show all 254 references

Cited by

Sorted by citations

See all 374

Related

Metadata

Authors
Ferreira, S. T., Lourenco, M. V., Oliveira, M. M., & De Felice, F. G.
Affiliations
Universidade Federal do Rio de Janeiro (BR)
Corresponding author
Ferreira, Sergio T.
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2015-05-26
Volume
9
Pages
191-191
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2015.00191
PMC
PMC4443025
OpenAlex
W1520284233
Cited by
373
References
254
Citations by year
2026: 23 · 2025: 24 · 2024: 16 · 2023: 40 · 2022: 38 · 2021: 51 · 2020: 45 · 2019: 33 · 2018: 40 · 2017: 38 · 2016: 23 · 2015: 2
FWCI
4.22
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
  • Institute for Translational Neuroscience
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta oligomers, synaptotoxicity, cognitive impairment, amyloid plaques, neuronal dysfunction, memory loss, Alzheimer's disease pathogenesis, Alzheimer's disease treatment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review