Non-fibrillar amyloid-beta peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity.

Amyloid-beta peptide (Abeta) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that Abeta has important physiological roles in addition to its pathological roles. We recently demonstrated that Abeta42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between Abeta42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar Abeta42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar Abeta42 on glutamate-induced neurotoxicity. Non-fibrillar Abeta42, but not fibrillar Abeta42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar Abeta42 decreased both neurotoxicity and increases in the intracellular Ca(2+) concentration induced by N-methyl-d-aspartate (NMDA), but not by alpha-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar Abeta42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

[1]  D. Selkoe,et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism , 1992, Nature.

[2]  D. Bennett,et al.  Paradoxical Upregulation of Glutamatergic Presynaptic Boutons during Mild Cognitive Impairment , 2007, The Journal of Neuroscience.

[3]  C. Peers,et al.  Physiological roles for amyloid β peptides , 2006 .

[4]  Xin Wu,et al.  Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model , 2002, Nature Neuroscience.

[5]  D. Selkoe,et al.  Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. , 2003, Annual review of pharmacology and toxicology.

[6]  T. Kihara,et al.  Amyloid beta-peptide preconditioning reduces glutamate-induced neurotoxicity by promoting endocytosis of NMDA receptor. , 2006, Biochemical and biophysical research communications.

[7]  M. Kirkitadze,et al.  Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Walsh,et al.  Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. , 1997, The Journal of biological chemistry.

[9]  C. Peers,et al.  Physiological roles for amyloid beta peptides. , 2006, The Journal of physiology.

[10]  C. Masters,et al.  Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease , 1999, Annals of neurology.

[11]  D. Choi.  Excitotoxic cell death. , 1992, Journal of neurobiology.

[12]  J. Rossier,et al.  Subunit composition at the single-cell level explains functional properties of a glutamate-gated channel , 1994, Neuron.

[13]  D L Price,et al.  Alzheimer's disease: genetic studies and transgenic models. , 1998, Annual review of genetics.

[14]  P. Dodd,et al.  Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease , 2004, Neurochemistry International.

[15]  D. Selkoe,et al.  Alzheimer's Disease: A Central Role for Amyloid , 1994, Journal of neuropathology and experimental neurology.

[16]  R. Malinow,et al.  APP Processing and Synaptic Function , 2003, Neuron.

[17]  Allan I. Levey,et al.  Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo , 1996, Neuron.

[18]  M. Kirkitadze,et al.  Amyloid b-protein (Ab) assembly: Ab40 and Ab42 oligomerize through distinct pathways , 2003 .

[19]  D. Walsh,et al.  Amyloid β-Protein Fibrillogenesis , 1997, The Journal of Biological Chemistry.

[20]  Weiming Xia,et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice , 1997, Nature Medicine.

[21]  D. Teplow,et al.  Amyloid beta-peptide is produced by cultured cells during normal metabolism. , 1992, Nature.

[22]  D. M. Robinson,et al.  Memantine , 2012, Drugs.

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

[24]  C. Peers,et al.  The Production of Amyloid β Peptide Is a Critical Requirement for the Viability of Central Neurons , 2003, The Journal of Neuroscience.