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J. A. Moncaster, R. D. Moir, L. Fu, A. Mocofanescu, S. Lu, W. Xu, E. Arnett, J. I. Clark, R. E. Tanzi, L. E. Goldstein; Early Detection of Alzheimer’s Disease-Linked Aß Peptide Accumulation in the Lens by Non-Invasive Quasi-Elastic Light Scattering. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4256.
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© ARVO (1962-2015); The Authors (2016-present)
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 ß-amyloid (Aß) in the brain that begins years before the onset of cognitive symptoms. Presymptomatic detection of the underlying disease process will accelerate clinical efficacy testing and facilitate early therapeutic intervention when emerging treatments are expected to be most effective and enduring. We previously identified Aß, 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.
Non-invasive infrared QLS, slit lamp stereophotomicroscopy, quantitative western blot, fluoro-ELISA, immunogold EM, tryptic digest MS sequencing.
In vivo, QLS was able to discriminate non-anesthetized Tg mice with clear lenses from age-matched non-anesthetized wild-type controls by 10 months of age before ß-amyloid pathology was detectable in the brain. We sequenced human Aß in Tg2576 mouse lens and demonstrated human Aß generation from AD-linked variant human amyloid precursor protein. Human Aß accumulated in the cytoplasm of Tg lens fiber cells as electron-dense microaggregates that scatter light. Human Aß promoted aggregation of mouse lens protein and corresponding QLS signal changes in vitro that replicated the QLS changes detected in Tg mice in vivo.
Our data support AD-linked Aß 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.
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