Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

Chung, Samuel

doi:10.5483/bmbrep.2009.42.8.467

Cited by 77 publications

(49 citation statements)

References 96 publications

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“…Unrelated to tau and amyloid-β, recent work suggests that lysosomal dysfunction in AD has a deleterious effect on FAT (Boland, et al, 2008, Lee, et al, 2011). While all of these pathogenic pathways warrant further investigation and discussion, this review focuses on pathways featuring abnormal activation of kinases and phosphatases, a major AD hallmark (Chung, 2009). …”

Section: Axonal Transport Defects In Admentioning

confidence: 99%

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Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

Kanaan

Pigino

Brady

et al. 2013

Experimental Neurology

186

138

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Alzheimer’s disease (AD) is characterized by progressive, age-dependent degeneration of neurons in the central nervous system. A large body of evidence indicates that neurons affected in AD follow a dying-back pattern of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death. Mechanisms underlying dying-back degeneration of neurons in AD remain elusive but several have been proposed, including deficits in fast axonal transport (FAT). Accordingly, genetic evidence linked alterations in FAT to dying-back degeneration of neurons, and FAT defects have been widely documented in various AD models. In light of these findings, we discuss experimental evidence linking several AD-related pathogenic polypeptides to aberrant activation of signaling pathways involved in the phosphoregulation of microtubule-based motor proteins. While each pathway appears to affect FAT in a unique manner, in the context of AD, many of these pathways might work synergistically to compromise the delivery of molecular components critical for the maintenance and function of synapses and axons. Therapeutic approaches aimed at preventing FAT deficits by normalizing the activity of specific protein kinases may help prevent degeneration of vulnerable neurons in AD.

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Section: Axonal Transport Defects In Admentioning

confidence: 99%

“…Dysfunction in any or all these regulatory mechanisms may be important to AD pathogenesis. Because alterations in kinase-based signaling pathways are widely recognized in AD (Chung, 2009), the remainder of this review focuses on the regulation of motor proteins by phosphorylation.…”

Section: Phosphotransferases Regulate Fast Axonal Transportmentioning

confidence: 99%

Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

Kanaan

Pigino

Brady

et al. 2013

Experimental Neurology

186

138

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“…Since these processes are essential for adequate cellular development and differentiation, intercellular communication, homeostasis, and apoptosis, they are usually tightly and transiently regulated (Manning et al, 2002). This fact becomes evident as abnormal phosphorylation events lead to unwanted substrate activity and have a causal role in many diseases, such as cancer and neurological disorders (Aggarwal et al, 2009;Chung, 2009).…”

Section: Kinome Profiling Of Cells On Pepchip Kinase Peptide Microarrmentioning

confidence: 99%

Intracellular signal transduction as a factor in the development of “Smart” biomaterials for bone tissue engineering

Zambuzzi

Coelho

Alves

et al. 2011

Biotech & Bioengineering

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Signal transduction involves studying the intracellular mechanisms that govern cellular responses to external stimuli such as hormones, cytokines, and also cell adhesion to biomaterials surfaces. Several events have been shown to be responsible for cellular adhesion and adaptation onto different surfaces. For instance, cytoskeletal rearrangements during cell adhesion require the recruitment of specific protein tyrosine kinases into focal adhesion structures that promote transient focal adhesion kinase and Src phosphorylations, initially modulating cell behavior. In addition, the phosphorylation of tyrosine (Y) residues have been generally accepted as a critical regulator of a wide range of cell-related processes, including cell proliferation, migration, differentiation, survival signalling, and energy metabolism. The understanding of the signaling involved on the mechanisms of osteoblast adhesion, proliferation, and differentiation on implant surfaces is fundamental for the successful design of novel "smart" materials, potentially decreasing the repair time, thereby allowing for faster patient rehabilitation.

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“…While neither our study nor prior studies (Chung, 2009, Liang, et al, 2010) differentiate between reductions in tau phosphorylation resulting from less Aβ accumulation or directly from modulation of calpain activity, either mechanism is potentially beneficial in the disease. Pathologically important disruption of calpain activity, including dysregulation of tissue-specific calpain family members, can occur in a number of aging-related diseases, including type 2 diabetes, cataracts, muscular dystrophy, Parkinson’s disease, rheumatoid arthritis, ischemia, stroke and brain trauma, various platelet syndromes, hypertension, liver dysfunction and some types of cancer (Carragher, 2006, Zatz and Starling, 2005).…”

Section: Discussionmentioning

confidence: 54%

“…Multiple studies suggest that in post-mortem human AD brain the neuronal calpain system is upregulated (Grynspan, et al, 1997, Liu, et al, 2005, Nixon, 2003, Saito, et al, 1993), albeit these findings do not necessarily argue for a direct role for calpain activation in the disease. There are numerous studies, however, indicating that calpain activation may lead to pathological changes in tau phosphorylation both in vitro (Amadoro, et al, 2006, Chung, 2009, Lee, et al, 2000) and in vivo (Chung, 2009, Veeranna, et al, 2004), as well as alterations in APP metabolism in vitro (Klafki, et al, 1996, Mathews, et al, 2002b, Yamazaki, et al, 1997, Zhang, et al, 1999). The growing evidence from transgenic mouse models, including our study, that calpain activation can result from β-amyloid accumulation and/or altered Aβ levels argues that the calpain system responds to AD-related pathological changes in the brain (Liang, et al, 2010, Vaisid, et al, 2007), thus positioning calpains as having a role in both driving and responding to the disease.…”

Section: Discussionmentioning

confidence: 99%

Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice

Morales-Corraliza

Berger

Mazzella

et al. 2012

Neurobiology of Aging

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We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer’s disease (AD) β-amyloidosis, the APP23 mouse, reduces β-amyloid pathology and Aβ levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Aβ plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments when compared to APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Aβ plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with β-amyloid pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced ERK1/2 activity and tau phosphorylation when compared to APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Aβ pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop β-amyloid pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of β-amyloid pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.

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Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

Cited by 77 publications

References 96 publications

Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system

Intracellular signal transduction as a factor in the development of “Smart” biomaterials for bone tissue engineering

Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice

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