Abstract
Oligomers of the amyloid-β (Aβ) protein are suspected to be responsible for the development and progression of Alzheimer’s disease. Thus, the development of compounds that are able to eliminate already formed toxic Aβ oligomers is very desirable. Here, we describe the in vivo efficacy of the compound RD2, which was developed to directly and specifically eliminate toxic Aβ oligomers. In a truly therapeutic, rather than a preventive study, oral treatment with RD2 was able to reverse cognitive deficits and significantly reduce Aβ pathology in old-aged transgenic Alzheimer’s Disease mice with full-blown pathology and behavioral deficits. For the first time, we demonstrate the in vivo target engagement of RD2 by showing a significant reduction of Aβ oligomers in the brains of RD2-treated mice compared to placebo-treated mice. The correlation of Aβ elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice support the hypothesis that Aβ oligomers are relevant not only for disease development and progression, but also offer a promising target for the causal treatment of Alzheimer’s disease.
Highlights
The most common form of dementia worldwide is Alzheimer’s disease (AD), a progressive and incurable neurodegenerative disease [1,2,3]
Monomeric Aβ, a cleavage product of the proteolytic processing of the amyloid protein precursor (APP) by a β- and a γ-secretase, aggregates into Aβ oligomers and into amyloid fibrils, which are found in AD plaques and were previously considered to be the cause of cognitive deficits [8]
Ten APP/PS1 mice were given a jelly without RD2
Summary
The most common form of dementia worldwide is Alzheimer’s disease (AD), a progressive and incurable neurodegenerative disease [1,2,3]. There is an urgent need for the development of new therapeutic strategies for the causal treatment of AD [5]. The pathological hallmarks of AD are neurofibrillary tangles, consisting of hyperphosphorylated tau protein, progressive neurodegeneration, and the accumulation of toxic amyloid-β (Aβ) species [1, 5]. The central dogma for the development of AD is the so-called amyloid cascade hypothesis [6, 7]. It states that an imbalance between the production and clearance of Aβ in the brain of affected people is responsible for neurodegeneration and dementia. More and more evidence exists which suggests that instead of Aβ
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