Synthetic Aβ oligomers (Aβ(1-42) globulomer) modulate presynaptic calcium currents: prevention of Aβ-induced synaptic deficits by calcium channel blockers.

Alzheimer's disease is accompanied by increased brain levels of soluble amyloid-β (Aβ) oligomers. It has been suggested that oligomers directly impair synaptic function, thereby causing cognitive deficits in Alzheimer's disease patients. Recently, it has been shown that synthetic Aβ oligomers directly modulate P/Q-type calcium channels, possibly leading to excitotoxic cascades and subsequent synaptic decline. Using whole-cell recordings we studied the modulation of recombinant presynaptic calcium channels in HEK293 cells after application of a stable Aβ oligomer preparation (Aβ1-42 globulomer). Aβ globulomer shifted the half-activation voltage of P/Q-type and N-type calcium channels to more hyperpolarized values (by 11.5 and 7.5 mV). Application of non-aggregated Aβ peptides had no effect. We then analyzed the potential of calcium channel blockers to prevent Aβ globulomer-induced synaptic decline in hippocampal slice cultures. Specific block of P/Q-type or N-type calcium channels with peptide toxins completely reversed Aβ globulomer-induced deficits in glutamatergic neurotransmission. Two state-dependent low molecular weight P/Q-type and N-type calcium channel blockers also protected neurons from Aβ-induced alterations. On the contrary, inhibition of L-type calcium channels failed to reverse the deficit. Our data show that Aβ globulomer directly modulates recombinant P/Q-type and N-type calcium channels in HEK293 cells. Block of presynaptic calcium channels with both state-dependent and state-independent modulators can reverse Aβ-induced functional deficits in synaptic transmission. These findings indicate that presynaptic calcium channel blockers may be a therapeutic strategy for the treatment of Alzheimer's disease.

[1]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[2]  J. Bockaert,et al.  Inhibition of voltage-gated Ca2+ channels by antazoline , 2002, Neuroreport.

[3]  I. Slutsky,et al.  Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses , 2009, Nature Neuroscience.

[4]  M. Ninomiya,et al.  α-Eudesmol, a P/Q-type Ca2+ channel blocker, inhibits neurogenic vasodilation and extravasation following electrical stimulation of trigeminal ganglion , 2000, Brain Research.

[5]  S. DeKosky,et al.  Structural correlates of cognition in dementia: quantification and assessment of synapse change. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[6]  Z. Henderson,et al.  Enhancement of (45)Ca(2+) influx and voltage-dependent Ca(2+) channel activity by beta-amyloid-(1-40) in rat cortical synaptosomes and cultured cortical neurons. Modulation by the proinflammatory cytokine interleukin-1beta. , 2000, The Journal of biological chemistry.

[7]  D. Muller,et al.  A simple method for organotypic cultures of nervous tissue , 1991, Journal of Neuroscience Methods.

[8]  G. Mealing,et al.  Neuroprotective effects of omega-Aga-IVA against in vitro ischaemia in the rat hippocampal slice. , 1995, Neuroreport.

[9]  A. Ferreira,et al.  Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons , 2007, Neuroscience.

[10]  R. Kayed,et al.  Soluble Aβ oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer's disease brain , 2005, Brain Research.

[11]  A. Akaike,et al.  Identification and Characterization of Novel Human Cav2.2 (α1B) Calcium Channel Variants Lacking the Synaptic Protein Interaction Site , 2002, The Journal of Neuroscience.

[12]  V. Gribkoff,et al.  Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. , 2005, Biochemical pharmacology.

[13]  M. Scheideler,et al.  Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice , 1996, Psychopharmacology.

[14]  Keith A. Vossel,et al.  Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model , 2012, Proceedings of the National Academy of Sciences.

[15]  E. Masliah,et al.  Diffuse plaques do not accentuate synapse loss in Alzheimer's disease. , 1990, The American journal of pathology.

[16]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[17]  K. Blennow,et al.  Synaptic pathology in Alzheimer's disease: Relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele , 2005, Journal of Neural Transmission.

[18]  A. Draguhn,et al.  Amyloid β Oligomers (Aβ1–42 Globulomer) Suppress Spontaneous Synaptic Activity by Inhibition of P/Q-Type Calcium Currents , 2008, The Journal of Neuroscience.

[19]  Adriana B Ferreira,et al.  Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. , 2005, The Journal of biological chemistry.

[20]  W. Wadman,et al.  Development of HVA and LVA calcium currents in pyramidal CA1 neurons in the hippocampus of the rat. , 1997, Brain research. Developmental brain research.

[21]  Anatol C. Kreitzer,et al.  Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer's Disease , 2007, Neuron.

[22]  K. Ashe.  Learning and memory in transgenic mice modeling Alzheimer's disease. , 2001, Learning & memory.

[23]  K. Elmslie,et al.  The separation of antagonist from agonist effects of trisubstituted purines on CaV2.2 (N‐type) channels , 2008, Journal of neurochemistry.

[24]  M. Moskowitz,et al.  Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the α1A subunit of P/Q type calcium channels , 1999, Neuroscience.

[25]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[26]  Bernardo L Sabatini,et al.  Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway , 2007, The Journal of Neuroscience.

[27]  Lin Chen,et al.  Evaluation of β-amyloid peptide 25–35 on calcium homeostasis in cultured rat dorsal root ganglion neurons , 2002, Brain Research.

[28]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[29]  C. Fletcher,et al.  Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  L. Lue,et al.  Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease , 1999 .

[31]  K. Zou,et al.  A Novel Function of Monomeric Amyloid β-Protein Serving as an Antioxidant Molecule against Metal-Induced Oxidative Damage , 2002, The Journal of Neuroscience.

[32]  D. Selkoe,et al.  Effects of secreted oligomers of amyloid β‐protein on hippocampal synaptic plasticity: a potent role for trimers , 2006, The Journal of physiology.

[33]  L. Zweifel,et al.  Systematic Identification of Splice Variants in Human P/Q-Type Channel α12.1 Subunits: Implications for Current Density and Ca2+-Dependent Inactivation , 2002, The Journal of Neuroscience.

[34]  K. Imahori,et al.  Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid β-Protein (Aβ) Assembly from Alzheimer Disease Brains* , 2009, The Journal of Biological Chemistry.

[35]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[36]  H. Schoemaker,et al.  A β‐amyloid oligomer directly modulates P/Q‐type calcium currents in Xenopus oocytes , 2012, British journal of pharmacology.

[37]  W. Klein,et al.  Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease , 2007, The Journal of Neuroscience.

[38]  R. Martins,et al.  Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β , 2003, Brain Research Reviews.

[39]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Selkoe,et al.  Natural oligomers of the amyloid-β protein specifically disrupt cognitive function , 2005, Nature Neuroscience.

[41]  Marc G. Weisskopf,et al.  The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation , 1994, Neuron.

[42]  R. Tsien,et al.  Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. , 1994, Science.

[43]  Seth Love,et al.  Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial , 2008, The Lancet.

[44]  R. Nicoll,et al.  Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Zornow,et al.  Transient brain ischemia in rabbits: the effect of ω-conopeptide MVIIC on hippocampal excitatory amino acids , 1995, Brain Research.

[46]  P. Keller,et al.  Globular amyloid β‐peptide1−42 oligomer − a homogenous and stable neuropathological protein in Alzheimer's disease , 2005 .

[47]  H. Schoemaker,et al.  Inhibition of calpain prevents NMDA‐induced cell death and β‐amyloid‐induced synaptic dysfunction in hippocampal slice cultures , 2010, British journal of pharmacology.

[48]  H. Mizusawa,et al.  Novel Cav2.1 Splice Variants Isolated from Purkinje Cells Do Not Generate P-type Ca2+ Current* , 2002, The Journal of Biological Chemistry.

[49]  A. Draguhn,et al.  Synaptic transmission is impaired prior to plaque formation in amyloid precursor protein–overexpressing mice without altering behaviorally-correlated sharp wave–ripple complexes , 2009, Neuroscience.

[50]  T. Snutch,et al.  Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels , 2000, Neuropharmacology.

[51]  Peter H. Barry,et al.  JPCalc, a software package for calculating liquid junction potential corrections in patch-clamp, intracellular, epithelial and bilayer measurements and for correcting junction potential measurements , 1994, Journal of Neuroscience Methods.

[52]  A. Palmeri,et al.  Picomolar Amyloid-β Positively Modulates Synaptic Plasticity and Memory in Hippocampus , 2008, The Journal of Neuroscience.

[53]  F. Conti,et al.  The binding of kappa-Conotoxin PVIIA and fast C-type inactivation of Shaker K+ channels are mutually exclusive. , 2004, Biophysical journal.

[54]  Z. Henderson,et al.  Modulation of Ca2+ channel currents in primary cultures of rat cortical neurones by amyloid β protein (1–40) is dependent on solubility status , 2002, Brain Research.

[55]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[56]  T. Soong,et al.  Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels , 1999, Nature Neuroscience.

[57]  J Korf,et al.  β‐Amyloid neurotoxicity is mediated by a glutamate‐triggered excitotoxic cascade in rat nucleus basalis , 2000, The European journal of neuroscience.

[58]  V. Nimmrich,et al.  Is Alzheimer's Disease a Result of Presynaptic Failure? - Synaptic Dysfunctions Induced by Oligomeric β-Amyloid , 2009, Reviews in the neurosciences.

[59]  J. Mariani,et al.  Aβ(25–35) and Aβ(1–40) act on different calcium channels in CA1 hippocampal neurons , 2002 .

[60]  F. LaFerla,et al.  Role of calcium in the pathogenesis of Alzheimer's disease and transgenic models. , 2007, Sub-cellular biochemistry.

[61]  G. Bulaj,et al.  Neuroprotective and cardioprotective conopeptides: an emerging class of drug leads. , 2009, Current opinion in drug discovery & development.