Biochemical and Biophysical Research Communications
Mechanism of membrane depolarization caused by the Alzheimer Aβ1–42 peptide☆
Section snippets
Materials and methods
mGluR Antagonists and agonists were obtained from Tocris Cookson Ltd., pertussis toxin and cholera toxin were from Sigma, Inc. Stock solutions of Aβ1–42 were prepared as described [4]. Experimental samples were prepared by diluting the stock solution of Aβ1–42 to (unless otherwise noted) in Tyrode's/2Ca buffer (150 mM NaCl, 3 mM KCl, 10 mM HEPES, pH 7.4, 2 mM CaCl2, 10 mM d-glucose, pH 7.4). Seed-free Aβ1–42 was prepared as described by Fezoui et al. [14] for Aβ1–40. In our case the seed-free
Results and discussion
In differentiated hNT neuronal cells, we find that the pre-aggregated Alzheimer peptide Aβ(1–42, aggr.) causes a large membrane depolarization. The peptide had been allowed to aggregate in Tyrode's/2Ca buffer at 37 °C and pH 7.4 for 48 h. For example, when Aβ(1–42, aggr.) at is added to the cells in the presence of the slow-acting voltage-sensitive fluorescent dye DiBAC4(3), there is an immediate sharp increase in fluorescence (Fig. 1A), indicating cell membrane depolarization. The new
Acknowledgements
This work was supported by the John & Dorothy Wilson Fund and by the Kurt & Johanna Immerwahr Fund for Alzheimer Research at MIT. Part of the work (V.T.) was funded by the MIT Undergraduate Research Opportunities Program. We are grateful to Prof. Elazer Edelman, Harvard-MIT Health Sciences Division, for allowing us to use his Fluoroskan II fluorometer, and to Prof. Jonathan King, Biology, MIT, for the use of his Hitachi fluorimeter. We gratefully acknowledge the many helpful discussions with
References (21)
Clearing the brain's amyloid cobwebs
Neuron
(2001)- et al.
Mechanism and prevention of neurotoxicity caused by beta-amyloid peptides: relation to Alzheimer's disease
Brain Res.
(1997) - et al.
Beta-amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease
Trends Neurosci.
(1993) - et al.
Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF
Brain Res.
(1993) - et al.
An anion binding site that regulates the glutamate transporter of synaptic vesicles
J. Biol. Chem.
(1993) - et al.
Genistein inhibits protein histidine kinase
J. Biol. Chem.
(1992) - et al.
Eliminating membrane depolarization caused by the Alzheimer peptide Aβ(1–42, aggr.)
Biochem. Biophys. Res. Commun.
(2002) - et al.
Structural model for the beta-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide
Nat. Struct. Biol.
(1995) - et al.
Elimination of β-amyloid neurotoxicity
J. Alzheimer Disease
(2000) - et al.
The toxicity in vitro of β-amyloidprotein
Biochem. J.
(1995)
Cited by (62)
Metabotropic glutamate receptors: the potential for therapeutic applications in Alzheimer's disease
2018, Current Opinion in PharmacologyMetabotropic glutamate receptors and neurodegenerative diseases
2017, Pharmacological ResearchCitation Excerpt :However, the exact role of mGluR1 in AD is rather complex. It has been shown that the Aβ-induced membrane depolarization may be due to the activation of Group I mGluRs (especially mGluR1) by the aggregated form of Aβ42 [105]. The data presented indicate that the depolarization pathway induced by Aβ is caused by the activation of mGluR1/G-protein signaling together with the activation of certain tyrosine kinases (mainly TrkA and EGF-receptor) and the modulation of K+ currents [105,119].
Identifying microRNAs related to Alzheimer's disease from differential methylation signatures
2016, Gene ReportsCitation Excerpt :Recent studies have confirmed a link between morphological and functional changes arising in the monoaminergic ascending system, predominantly in norepinephrine and serotonin, and the pathophysiology of AD (Trillo et al., 2013a, 2013b). Another example of Aβ42 toxicity is revealed when dramatic membrane depolarization in neuronal cells is caused (through the activation of metabotropic glutamate receptors) with the pre-incubation of this insoluble oligomer (Blanchard et al., 2002). Decline in membrane depolarization is a critical molecular mechanism behind the cognitive decline observed in AD.
Mitochondrial emitted electromagnetic signals mediate retrograde signaling
2015, Medical HypothesesBexarotene reduces network excitability in models of Alzheimer's disease and epilepsy
2014, Neurobiology of AgingCitation Excerpt :The cellular mechanisms leading to the dynamic and potentially reversible component of dementia in Aβ-overexpression models of AD and their amelioration by bexarotene remain poorly understood. There is ample evidence at the single cell level for Aβ-linked defects in synaptic plasticity, and these are accompanied by circuit level network discharges and seizures in most experimental genetic models of AD (Blanchard et al., 2002; Minkeviciene et al., 2009; Mucke and Selkoe, 2012). Network hyperexcitability may arise from changes in intrinsic membrane properties as well as synaptic and connectivity defects and all have been described in AD models (Palop and Mucke, 2010).
- ☆
Abbreviations: AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; D-AP5, 2-amino-5-phosphonovaleric acid; DiBAC4(3), bis-(1,3-dibutylbarbituric acid)trimethine oxonol; Fura-2 salt, ratiometric Ca2+ indicator–Na salt; hNT neurons, a human teratocarcinoma cell line differentiated with retinoic acid; NMDA, N-methyl-d-aspartate; NMDG+30, N-methyl-d-glucamine; Tyrode's/2Ca, Tyrode's solution with 2mM Ca2+.