Amyloid-Independent Mechanisms in Alzheimer's Disease Pathogenesis

Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2010; 30(45):14946-54. DOI: 10.1523/JNEUROSCI.4305-10.2010
Source: PubMed


Despite the progress of the past two decades, the cause of Alzheimer's disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid-β (Aβ) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that Aβ peptides are unlikely to be the sole factor in AD etiology. Evidence that Aβ/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.

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Available from: Nikolaos K Robakis, Jul 15, 2014
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    • "However, the studies show us that it is not the sole factor in AD etiology . Amyloid independent factors, such as AD-related genes, defective endo-lysosomal trafficking, altered intracellular signaling cascades, in addition to impaired neurotransmitter are also important factors that have key roles in the development of disease [30]. The cyclin-dependent kinase (Cdk5) and glycogen synthase kinase GSK3b have been shown to be involved in anomalous tau phosphorylation . "
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    ABSTRACT: Alzheimer's disease is a multifaceted brain disorder which involves various coupled irreversible, progressive biochemical reactions that significantly reduce quality of life as well as the actual life expectancy. Aging, genetic predispositions, head trauma, diabetes, cardiovascular disease, deficiencies in insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, high cholesterol level, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic dysfunction, high blood pressure, obesity, dietary habits, exercise, social engagement, and mental stress are noted among the risk factors of this disease. In this hypothesis review I would like to draw the attention on glucose-6-phosphate dehydrogenase deficiency and its relationship with Alzheimer's disease. This enzymopathy is the most common human congenital defect of metabolism and defined by decrease in NADPH+H(+) and reduced form of glutathione concentration and that might in turn, amplify oxidative stress due to essentiality of the enzyme. This most common enzymopathy may manifest itself in severe forms, however most of the individuals with this deficiency are not essentially symptomatic. To understand the sporadic Alzheimer's disease, the writer of this paper thinks that, looking into a crystal ball might not yield much of a benefit but glucose-6-phosphate dehydrogenase deficiency could effortlessly give some clues. Copyright © 2015. Published by Elsevier Ltd.
    Medical Hypotheses 05/2015; 85(2). DOI:10.1016/j.mehy.2015.05.006 · 1.07 Impact Factor
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    • "There is compelling data to demonstrate that increased levels of Aβ compromise multiple cellular pathways. Thus, the downstream cognitive symptoms can be caused by non-Aβ factors including oxidative stress, inflammation, mitochondrial dysfunction, and lipid perturbations (Pimplikar et al., 2010). At the same time, emerging data from multiple animal studies and clinical investigations suggest a tight interconnection between Aβ and pTau, and therefore, development of strategies to reduce levels of both could be beneficial (Jack and Holtzman, 2013; Mondragon-Rodriguez et al., 2012). "
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    ABSTRACT: Development of therapeutic strategies to prevent Alzheimer's disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.
    03/2015; 82(4). DOI:10.1016/j.ebiom.2015.03.009
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    • "Amyloid-␤ Protein 331 A␤-independent factors [24] [30] [31]. Thus, the idea that AD may be caused by A␤PP-derived fragments, and not necessarily only by A␤ peptides, has gained momentum [32], notably because it was shown that both extracellular and intracellular fragments of A␤PP can trigger neuronal damage [33] [34]. "
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    ABSTRACT: Alzheimer's disease (AD) affects almost 35 million people worldwide. One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-β (Aβ) peptides. These peptides derive from the amyloidogenic proteolytic processing of the amyloid-β protein precursor (AβPP), through the sequential action of β- and γ-secretases. However, AβPP can also be cleaved by a non-amyloidogenic pathway, involving an α-secretase, and in this case the Aβ formation is precluded. The production of Aβ and of other AβPP catabolites depends on the spatial and temporal co-localization of AβPP with α- or β-secretases and γ-secretase, which traffic through the secretory pathway in a highly regulated manner. Disturbances on AβPP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. In this article, we critically review the recent knowledge about the trafficking and co-localization AβPP and related secretases in the brain under physiological and AD conditions. A particular focus is given to data concerning the distribution of AβPP and secretases in different types of synapses relatively to other neuronal or glial localizations. Furthermore, we discuss some possible signals that govern the dynamic encounter of AβPP with each group of secretases, such as AβPP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. The knowledge of key signals that are responsible for the shifting of AβPP processing away from α-secretases and toward the β-secretases might be useful to develop AD therapeutic strategies.
    Journal of Alzheimer's disease: JAD 01/2015; 45(2). DOI:10.3233/JAD-142730 · 4.15 Impact Factor
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