title: Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease.
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.
authors: Biological Sciences, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8, Toronto, ON, Canada.
authors: Christopher D
authors: CD
authors: Morrone
authors: Physical Sciences, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada.
authors: Lynsie A M
authors: LA
authors: Thomason
authors: Biological Sciences, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada.
authors: Mary E
authors: ME
authors: Brown
authors: Biological Sciences, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8, Toronto, ON, Canada.
authors: Isabelle
authors: I
authors: Aubert
authors: Biological Sciences, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8, Toronto, ON, Canada.
authors: JoAnne
authors: J
authors: McLaurin
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D055495:Neurogenesis
chemical_list: D016229:Amyloid beta-Peptides; D009414:Nerve Growth Factors