In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity

• Published in: Neurobiology of disease 2002-11, Vol.11 (2), p.330-340
• Main Authors: Kumar-Singh, Samir, Julliams, Ann, Nuydens, Rony, Ceuterick, Chantal, Labeur, Christine, Serneels, Sally, Vennekens, Krist'l, Van Osta, Peter, Geerts, Hugo, De Strooper, Bart, Van Broeckhoven, Christine
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; amyloid precursor protein; amyloid β; Animals; Belgium; Brain - metabolism; Brain - pathology; Brain - physiopathology; Cell Death - drug effects; Cell Death - genetics; Cells, Cultured; cerebral amyloid angiopathy; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Cytoskeleton - pathology; Humans; Kinetics; Mutation - genetics; Netherlands; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; neurotoxicity; Neurotoxins - toxicity; Peptide Fragments - toxicity; phosphorylation; Phosphorylation - drug effects; Rats; SH-SY5Y cells; Solubility; Stroke - genetics; Stroke - metabolism; Stroke - physiopathology; tau; tau Proteins - drug effects; tau Proteins - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1006/nbdi.2002.0529

Mutations in the β-amyloid (Aβ) sequence of the amyloid precursor protein gene ( APP) present with variable disease phenotypes. While patients with the Dutch APP mutation (E693Q) have predominantly hemorrhagic strokes, Flemish APP (A692G) patients develop both strokes and Alzheimer's disease (AD). To determine whether these diverse clinical and pathological presentations are due to mutant Aβ or APP, we studied the effect of Flemish, Dutch, and wild-type Aβ/APP on phosphorylation of specific tau epitopes observed in AD. No effect was observed in differentiated SH-SY5Y cells either stably expressing APP or treated with synthetic Aβ 12–42. However, we did observe a paradoxical temporal difference in the neurotoxic potential of mutant and wild-type Aβ. While long 24-h incubation at physiological levels of Aβ (2 μM) showed a higher amount of apoptosis for Dutch Aβ, a short 2-h incubation showed elevated apoptosis for Flemish and wild-type Aβ. The altered aggregating properties of Aβ, with Dutch Aβ aggregating faster and Flemish Aβ slower than wild type, elucidated a discrete two-phase Aβ neurotoxicity. We propose here that, at least in vitro, Aβ might be neurotoxic in an initial phase due to its soluble oligomeric or other early toxic Aβ intermediate(s), which is perhaps distinct from the late neurotoxicity incurred by aggregated larger assemblies of Aβ.