Efficacy and Toxicity of Clioquinol Treatment and A-beta42 Inoculation in the APP/PSI Mouse Model of Alzheimer's Disease

Yi-Hong      Zhang; James      Raymick; Sumit      Sarkar; Debomoy K.      Lahiri; Balmiki      Ray; David      Holtzman; Melanie      Dumas; Larry C.      Schmued

doi:10.2174/1567205011310050005

Abstract

Alzheimer’s disease (AD), the most common human neurodegenerative disease, is characterized pathologically by numerous deposits of amyloid plaques in the brain. Systemic administration of clioquinol (CQ) and inoculation with amyloid-beta42 (Aβ42) vaccines have been demonstrated to significantly inhibit deposits of amyloid in AD brains. However, each of these treatments has also been reported to be neurotoxic. The generation of transgenic mice models of AD has made it possible to study aspects of this disease employing experimental animals. In the present study, we investigated the efficacy and toxicity of CQ and Aβ42 vaccine in a transgenic AD (APP/PS1) mouse model. Our results confirmed that both CQ and Aβ42 vaccine were effective in significantly reducing the deposits of amyloid in the brains of transgenic AD mice. We also report here that systemic CQ induces myelinopathies in the dorsal lateral geniculate nucleus (DLG), which was almost devoid of amyloid plaques and is the primary site of retinal efferent projections via the optic nerve. This is the first report that systemic administration of CQ causes myelinopathies in the central nervous system (CNS) of a transgenic AD mouse model as well as wild-type mice. Inoculation with an Aβ42 vaccine was also found, for the first time, to result in a significant increase in plaque-independent astrocytic hyperplasia in the dorsal part of the lateral septal nucleus (LSD) which was also devoid of plaques, reflecting potential brain inflammatory processes.

Keywords: Alzheimer’s disease, amyloid plaque, transgenic mice, clioquinol, amyloid-beta42 vaccine, myelinopathy, astrocytes.

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