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

• Main Authors: Samir Kumar-Singh, Ann Julliams, Rony Nuydens, Chantal Ceuterick, Christine Labeur, Sally Serneels, Krist'l Vennekens, Peter Van Osta, Hugo Geerts, Bart De Strooper, Christine Van Broeckhoven
• Format: Article
• Language: English
• Published: Elsevier 2002-11-01
• Series: Neurobiology of Disease
• Subjects: Alzheimer's disease; cerebral amyloid angiopathy; tau; phosphorylation; amyloid β; amyloid precursor protein
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996102905292

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 Aβ12–42. 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.