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

ABSTRACT 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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    • "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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    • "Lysosomal activity is essential for complete degradation of cargo in the autophagic pathway. Given the fact that the pathology of AD is accompanied by a lysosomal dysfunction (for review, see [18]), we have investigated the potential effect of sA␤PP␣ on the crosstalk between proteasomal and autophagic protein degradation machineries. Employing primary fibroblasts IMR90, HEK 293 as well as rat primary hippocampal neurons, we investigated the efficacy of sA␤PP␣ on the intracellular adaptation to proteotoxic stress. "
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    ABSTRACT: Alzheimer's disease (AD) is the major age-associated form of dementia characterized by gradual cognitive decline. Aberrant cleavage of the amyloid-β protein precursor (AβPP) is thought to play an important role in the pathology of this disease. Two principal AβPP processing pathways exist: amyloidogenic cleavage of AβPP resulting in production of the soluble N-terminal fragment sAβPPβ, amyloid-β (Aβ), which accumulates in AD brain, and the AβPP intracellular domain (AICD) sAβPPα, p3 and AICD are generated in the non-amyloidogenic pathway. Prevalence of amyloidogenic versus non-amylodogenic processing leads to depletion of sAβPPα and an increase in Aβ. Although sAβPPα is a well-accepted neurotrophic protein molecular effects of this fragment remains unknown. Different studies reported impaired protein degradation pathways in AD brain, pointing to a role of disturbed proteasomal activity in the pathogenesis of this disease. Here we studied the possible role of sAβPPα in Bag3-mediated selective macroautophagy and proteasomal degradation. Employing human IMR90 cells, HEK 293 cells, and primary neurons, we demonstrate that sAβPPα prevents the proteotoxic stress-induced increase of Bag3 at the protein and at the mRNA level indicating a transcriptional regulation. Intriguingly, p62 and LC3, two other key players of autophagy, were not affected. Moreover, the formation and the accumulation of disease-related protein aggregates were significantly reduced by sAβPPα. Interestingly, there was a significant increase of proteasomal activity by sAβPPα as demonstrated by using various proteasome substrates. Our findings demonstrate that sAβPPα modulates Bag3 expression, aggresome formation, and proteasomal activity, thereby providing first evidence for a function of sAβPPα in the regulation of proteostasis.
    Journal of Alzheimer's disease: JAD 10/2014; 44(3). DOI:10.3233/JAD-140600 · 4.15 Impact Factor
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