2. Academic Validation
  3. The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression

The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression

  • Sci Rep. 2021 Jan 11;11(1):431. doi: 10.1038/s41598-020-80164-w.
Maa O Quartey 1,  Jennifer N K Nyarko 1,  Jason M Maley 2,  Jocelyn R Barnes 3,  Maria A C Bolanos 4,  Ryan M Heistad 1,  Kaeli J Knudsen 1,  Paul R Pennington 1,  Josef Buttigieg 4,  Carlos E De Carvalho 5,  Scot C Leary 6,  Matthew P Parsons 3,  Darrell D Mousseau 7
Affiliations

Affiliations

  • 1 Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada.
  • 2 Saskatchewan Structural Sciences Centre, University of Saskatchewan, Saskatoon, SK, Canada.
  • 3 Division of BioMedical Sciences (Neurosciences), Memorial University of Newfoundland, St. John's, NL, Canada.
  • 4 Department of Biology, University of Regina, Regina, SK, Canada.
  • 5 Department of Biology, University of Saskatchewan, Saskatoon, SK, Canada.
  • 6 Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
  • 7 Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada. darrell.mousseau@usask.ca.
PMID: 33432101 DOI: 10.1038/s41598-020-80164-w
Abstract

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).

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