| Autor: |
Quartey MO; Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada., Nyarko JNK; Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada., Maley JM; Saskatchewan Structural Sciences Centre, University of Saskatchewan, Saskatoon, SK, Canada., Barnes JR; Division of BioMedical Sciences (Neurosciences), Memorial University of Newfoundland, St. John's, NL, Canada., Bolanos MAC; Department of Biology, University of Regina, Regina, SK, Canada., Heistad RM; Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada., Knudsen KJ; Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada., Pennington PR; Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada., Buttigieg J; Department of Biology, University of Regina, Regina, SK, Canada., De Carvalho CE; Department of Biology, University of Saskatchewan, Saskatoon, SK, Canada., Leary SC; Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada., Parsons MP; Division of BioMedical Sciences (Neurosciences), Memorial University of Newfoundland, St. John's, NL, Canada., Mousseau DD; Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada. darrell.mousseau@usask.ca. |
| Abstrakt: |
The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1-38), interacts with the AD-related variant, Aβ(1-42), and the predominant physiological variant, Aβ(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1-38) interacts differently with Aβ(1-40) and Aβ(1-42) and, in general, Aβ(1-38) interferes with the conversion of Aβ(1-42) to a β-sheet-rich aggregate. Functionally, Aβ(1-38) reverses the negative impact of Aβ(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1-42) phenotype in Caenorhabditis elegans. Aβ(1-38) also reverses any loss of MTT conversion induced by Aβ(1-40) and Aβ(1-42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1-38) and Aβ(1-42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1-42)/Aβ(1-38) [and Aβ(1-42)/Aβ(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1-42). |
