Abstract
Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer’s disease (AD)-like pathology, specifically Aβ-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Aβ pathology with scyllo-inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of scyllo-inositol treatment. The prolonged exposure to Aβ-pathology leads to deficits in the neurogenic niche, thus targeting Aβ alone is insufficient to rescue neurogenesis. To support the neurogenic niche, we combined scyllo-inositol treatment with leteprinim potassium (neotrofin), the latter of which stimulates neurotrophin expression. We show that the combination treatment of scyllo-inositol and neotrofin enhances neuronal survival and differentiation. We propose this proof of concept combination therapy of targeting Aβ-pathology and neurotrophin deficits as a potential treatment for AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease that most commonly affects the elderly population [1]
To determine the role of Aβ-toxicity on adult hippocampal neurogenesis, we examined the effect of the Aβ-targeting compound, scyllo-inositol, in Tg mice at different stages of pathology
We demonstrate that in early AD-like pathology, reduction of Aβ is sufficient to restore neurogenesis to levels of NTg mice, in more established disease no effect was observed
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease that most commonly affects the elderly population [1]. Many have failed to meet primary cognitive endpoints, possibly as a result of intervention after the long prodromal phase of AD that relates
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