Abstract

In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.

Highlights

  • Down syndrome (DS), or trisomy 21, affects one in 733 newborns [1,2,3,4]

  • We demonstrate that the DS-01 vaccine was potent, safe and effective in a mouse model of DS

  • Vaccinated Ts65Dn brains demonstrated consistent trends for reductions in Aβ42 and Aβ40 resulting in values that were no longer statistically different with respect to 2N values

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Summary

Introduction

Down syndrome (DS), or trisomy 21, affects one in 733 newborns [1,2,3,4]. In addition to cognitive dysfunction during childhood, those with DS are predisposed to Alzheimer disease (AD). Mature neuritic plaques and neurofibrillary tangles are present by age 40 in DS [5] and about 60% have dementia by age ~60 [6,7]—i.e. approximately 25 years earlier than those with late onset AD. Among human chromosome 21 (HSA 21) genes, increased dose of the gene for APP and the β-amyloid (Aβ) have been shown to be necessary for the emergence of AD-like symptoms in DS [8,9]. Outside the DS context, APP gene dose is sufficient to cause AD, as demonstrated in several families harboring a duplication of the APP gene [10,11]. The age of onset of dementia in these families is similar to DS [12,13].

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