In vivo Early Detection of Alzheimer’s Disease-Linked Aβ Peptide Accumulation in the Lens Using Quasi-Elastic Light Scattering

Abstract

Purpose: : Alzheimer’s disease (AD) is the most common form of age-related dementia and the eighth leading cause of US deaths. AD is characterized by excessive accumulation of β-amyloid (Aβ) in the brain that begins years before the onset of cognitive symptoms. Early detection of the underlying disease process will facilitate early therapeutic intervention when treatments are expected to be most effective and enduring. We previously identified Aβ, AD-linked amyloid pathology, and co-localizing supranuclear cataracts (SNC) in the lenses of patients with AD (Goldstein et al., Lancet, 2003) and Down syndrome (Goldstein et al., ARVO, 2006). Here, we developed and tested low-energy infrared laser quasi-elastic light scattering (QLS) technology for early quantitative detection and monitoring of AD-linked amyloid lens pathology in vivo.

Methods: : Non-invasive infrared QLS, slit lamp stereophotomicroscopy, quantitative western blot, fluoro-ELISA, immunogold EM, tryptic digest MS sequencing, immunohistochemistry and amyloid histochemistry.

Results: : Using the mouse model of Alzheimer’s Disease (Tg2576), we demonstrate the capability of in vivo QLS to discriminate non-anesthetized Tg mice from age-matched wild-type controls by 10 months of age before β-amyloid pathology was detectable in the brain. We sequenced human Aβ in Tg2576 mouse lens and demonstrated human Aβ generation in conditioned media from Tg lens but not Wt explant cultures. Human Aβ accumulated in the cytoplasm of Tg lens fiber cells as electron-dense microaggregates that scatter light. Human Aβ promoted aggregation of mouse lens protein that replicated QLS signal changes detected in vivo. Second-generation instruments incorporate confocal optics, autocorrelation spectroscopy, and high-affinity fluorescent amyloid-binding ligands.

Conclusions: : Our data support AD-linked Aβ aggregation in the lens as an optically accessible early AD biomarker and highlight the potential of non-invasive QLS for AD screening, diagnosis, and monitoring.

Keywords: detection • pathobiology • laser