Non-Invasive Detection of Age-Related and Alzheimer's Disease Linked Pathology in the Lenses of Human Subjects with Down Syndrome

Abstract

Purpose: The hallmark pathology in Alzheimer’s disease (AD) and Down syndrome is characterized by age-related deposition in the brain of amyloid β peptides (Aβ), which eventually results in plaque formation. Aβ is a cleavage product derived from the amyloid precursor protein (APP). We discovered that Aβ also accumulates in the supranuclear region of the lens in patients with AD (Goldstein et al., Lancet, 2003) and Down Syndrome (DS) (Moncaster et al., PloS One, 2010). DS is a common chromosomal disorder that carries 100% risk of early-onset AD and is the leading genetic cause of intellectual disability in humans. Triplication of chromosome 21 in DS invariably includes the APP gene (21q21) resulting in increased expression of APP and consequently Aβ.

Methods: In AD and DS lenses, Aβ accumulates as electron-dense intracellular aggregates (~5-100 nm) that distribute heterogeneously within the cytoplasm of supranuclear and deep cortical lens fiber cells. These Aβ lens aggregates qualify as Raleigh scattering centers that clinically manifest as distinctive specific supranuclear lens opacities and are phenotypically, anatomically, and biochemically distinguishable from common age-related nuclear cataracts. Here, we use Quasi-elastic Light Scattering (QLS) to detect and monitor these changes both in vitro and in vivo.

Results: Age-related and amyloid beta linked changes were observed in protein solutions and in an amyloid beta over-expression transgenic mouse model. Moreover we present preliminary results that suggest differences between DS patients and age-matched controls.

Conclusions: Changes in protein solutions can be attributed to post-translational modifications which occur over time and with other physiologically relevant perturbations. In the mouse model, we see differences between the transgenic mice compared to age-matched wild-type controls due to the over-expression of amyloid beta. Finally, from the initial results of the human clinical study there appear to be differences in particle characteristics between DS and control patients, and this will be explored further in future studies.

Keywords: 413 aging • 657 protein modifications-post translational