Lee E. Goldstein

Alzheimer's Disease Amyloid-β Links Lens and Brain Pathology in Down Syndrome

Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimers disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-β peptides (Aβ), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Aβ accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Aβ pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Aβ accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Aβ aggregates (∼5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Aβ in DS lenses. Incubation of synthetic Aβ with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Aβ accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.

IC-P-127

rescent signals with different lifetimes can be resolved in 3-dimensions. Screening of novel and existing near-infrared fluorophores resulted in several compounds with desirable properties as in vivo contrast agents. Using the new time-domain imaging algorithm, we will image transgenic mouse models of Alzheimer’s disease non-invasively to estimate plaque burden. Post-mortem confirmation of pathology will be used to correlate the in vivo results. Conclusions: These results, from simulations, to phantom measurements and in vivo imaging show that development of contrast agents and imaging approaches will allow sensitive imaging of amyloidbeta deposition in living APP mice with 3-dimensional information. This approach will accelerate pre-clinical drug development in animal models, and would ultimately translate to clinical imaging. Supported by NIH: EB00768, RR14075.

O3-01-02

Background: Passive immunization can consistently deliver the desired titers of therapeutic antibodies to Alzheimer’s Disease (AD) patients while avoiding many of the safety and tolerability issues associated with active vaccination. Intravenous Immunoglobulin (IVIg) is a very promising agent for this purpose. IVIg is a purified human natural immunoglobulin preparation with unique immune-modulating properties that contains elevated titers of polyclonal antibodies against the amyloid beta peptide (A ). IVIg has been used clinically for over 25 years as an approved treatment for various immune-deficiency and auto-immune disorders. Its established safety record can reduce the time and risks associated with its development as a treatment for AD. Methods: In two open-label pilot studies to date involving mild to moderate stage AD, monthly or bimonthly IVIg treatments for six months were well-tolerated, significantly improved dementia symptoms, increased plasma anti-A antibody titers and promoted clearance of A from the cerebrospinal fluid. Conclusions: Ongoing studies are shedding light on IVIg’s mechanisms of action, optimal dosing and the effects of chronic administration in the treatment of mild to moderate AD. The relatively high cost of IVIg, the need for intravenous administration, and current limitations in supplies of IVIg raise concerns about its equitable distribution if ongoing placebo-controlled clinical trials prove IVIg to be a suitable treatment for AD. Nevertheless, these issues are not likely to prove insurmountable, nor should they impede efforts to determine whether immunotherapy with natural human antibodies is an effective means of treating the symptoms and underlying pathology of AD.