Affiliations: The Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel | Program of Cognitive Neuroscience, Department of Psychology, Babeş-Bolyai University, Cluj-Napoca, CJ, Romania
Correspondence:
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Corresponding author: Daniel M. Michaelson, Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 3 6409624; Fax: +972 3 6407643; E-mail: dmichael@post.tau.ac.il.
Abstract: The amyloid-β (Aβ) peptide is a major constituent of the brain senile plaques that characterize Alzheimer's disease (AD). Converging observations led to the formulation of the amyloid hypothesis whereby the accumulation of soluble aggregates and insoluble Aβ deposits is the primary event in AD pathogenesis. Furthermore, the apoE4 isoform of apolipoprotein E, a major prevalent genetic risk factor of AD, is associated with increased Aβ deposition. To investigate the initial stages of the amyloid cascade in vivo and how this is affected by apoE4, we studied the effects of prolonged inhibition and subsequent reactivation of the Aβ-degrading enzyme, neprilysin, on aggregation and deposition of Aβ in apoE transgenic and control mice. The results revealed that Aβ deposition in vivo is initiated by aggregation of Aβ42, which is followed by reversible deposition of both Aβ42 and Aβ40, along with growth of the deposits, and by their subsequent irreversible fibrillization. The initiation of Aβ42 deposition is accelerated isoform-specifically by apoE4, whereas the growth and dissolution of the Aβ deposits as well as their fibrillization are similarly stimulated by the various apoE isoforms. Interestingly, Aβ deposition was associated with increased gliosis, which may reflect early pathological interactions of β with the brain's parenchyma.
