Abstract
Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer’s disease (AD) induced by a combination of oxidative stress, toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with the Aβ lowering AD experimental drugs (+)-phenserine and (−)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal–regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APPSWE), and retained in the presence of Aβ and oxidative stress challenge. (+)-Phenserine, together with its (−) enantiomer as well as its N1- and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).
Highlights
Alzheimer’s disease (AD), a progressive neurodegenerative condition resulting in memory loss and neuropsychiatric disturbances, is the most common form of dementia and afflicts in excess of 26 million people worldwide [1]
Substantial evidence indicates that toxic amyloid precursor protein (APP) metabolites and, in particular, amyloid-b peptide (Ab) induce oxidative stress and diminishing neurotrophic factors that lead to neuronal dysfunction and demise, and a decline in neurogenesis in the AD brain
Within the current study we assessed the actions of the clinical drug candidates (+)- and (2)-phenserine as the former has recently been reported to lower CSF levels of APP metabolites, Ab, tau and inflammatory markers in subjects with mild cognitive impairment [20], as well as to augment neurogenesis following progenitor cell transplantation in AD APP23 transgenic mice [26]
Summary
Alzheimer’s disease (AD), a progressive neurodegenerative condition resulting in memory loss and neuropsychiatric disturbances, is the most common form of dementia and afflicts in excess of 26 million people worldwide [1]. NFTs are formed from hyperphosphorylation of the microtubule-associated protein, tau The development of these pathological changes leads to oxidative stress and excitotoxicity, synaptic loss, of cholinergic neurons, changes in brain neurotrophin levels essential to support neuronal survival and neurogenesis, progressive cellular dysfunction and, eventually, neuronal death [7,8,10,11]. Each of these features provides a potential target to treat AD
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