Protein kinase C as a peripheral biomarker for Alzheimer’s disease

Barry, Jean de; Liegeois, Corinne; Jànoshàzi, Àgnes

doi:10.1016/j.exger.2009.10.015

Cited by 41 publications

(26 citation statements)

References 41 publications

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“…Recent studies indicate that PKC plays an important role in the pathophysiology of AD (Choi et al, 2006; Takashima, 2006; Takashima, 2006; Nelson et al, 2009), and increases in PKC activity can stimulate Aβ peptide production and tau protein hyperphosphorylation. In addition, other studies have demonstrated that GPCRs and PKA/PKC signaling pathways play an important role in the pathophysiology of AD (Lee et al, 2004; Choi et al, 2006; Takashima, 2006; da Cruz e Silva et al, 2009; Nelson et al, 2009; de Barry et al, 2010; Kim et al, 2011; Thathiah and De Strooper, 2011;; Thathiah et al, 2013). For example, some GPCRs directly influence the amyloid cascade through modulation of α-,β- and secretases, thereby affecting the proteolysis of the APP (Xu et al, 1996; Robert et al, 2001; Thathiah and De Strooper, 2011; Thathiah et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice

Dong

Wang²,

Zeng

et al. 2014

Psychopharmacology

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Rationale Previous studies indicate that psychosocial stressors could accelerate amyloid-β (Aβ) levels and accelerate plaque deposition in mouse models of Alzheimer disease (AD). Stressors enhanced the release of corticotrophin-releasing factor (CRF) and exogenous CRF administration mimicked the effects of stress on Aβ levels in mouse models of AD. However, whether CRF receptor 1 (CRF1) antagonists could influence the stress-induced acceleration of an AD-like process in mouse models has not been well studied. Objective We sought to examine whether CRF1 antagonists inhibit the effects of isolation stress on tissue Aβ levels, Aβ plaque deposition, and behaviors related to anxiety and memory in Tg2576 mice, and to investigate the molecular mechanism underlying such effects. Methods Cohorts of Tg2576 mouse pups were isolated or group-housed at 21 days of age, then the subgroups of these cohorts received daily intraperitoneal injections of the CRF1 antagonists, antalarmin or R121919 (5, 10 and 20 mg/kg), or vehicle for 1 week. Other cohorts of Tg2576 mouse pups were isolated or group housed at 21 days of age, and then at 4 months of age, subgroups of these mice were administered antalarmin (20 mg/kg) or vehicle in their drinking water for 6 months. Finally, cultured primary hippocampal neurons from regular Tg2576 pups (P0) were incubated with CRF (0.1, 1 and 10nM), antalarmin (100 nM) or H-89 (1 μM) for 48 hours. Brain tissues or cultured neurons were collected for histological and biochemical analyses, and behavioral measures were collected in the cohorts of mice that were chronically stressed. Results Administration of antalarmin at 20 mg/kg dose for 1 week significantly reduced Aβ1-42 levels in isolation stressed mice. Administration of antalarmin for 6 months significantly decreased plasma corticosterone levels, tissue Aβ1-42 levels and Aβ plaque deposition in the brain and blocked the effects of isolation stress on behaviors related to anxiety and memory. Finally, incubation of neurons with 100 nM antalarmin inhibited the ability of 10 nM CRF to increase Aβ1-42 levels and protein kinase A IIβ (PKAIIβ) expression. The effect of CRF1 on Aβ1-42 levels was also diminished by treatment with H-89, a c-AMP/PKA inhibitor. Conclusions These results suggest that CRF1 antagonists can slow an AD-like process in Tg2576 mice, and that the c-AMP/PKA signaling pathway may be involved in this effect.

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Section: Discussionmentioning

confidence: 99%

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice

Dong

Wang²,

Zeng

et al. 2014

Psychopharmacology

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“…If PKCβ is not translocated, it can hyperphosphorylate tau and substantially contribute to AD pathology [117]. Intracellular PKC has recently been proposed as an AD biomarker because dysfunctional PKC translocation can be successfully detected in red blood cells thereby mimicking the activation state of PKC within the brain [118]. …”

Section: Pkc and Admentioning

confidence: 99%

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Lucke‐Wold

Turner

Logsdon

et al. 2014

JAD

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Ischemic stroke and Alzheimer’s disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.

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“…In addition, protein kinase C (PKC), which has an important role in stimulating AβPP-Aβ peptide formation and tau hyperphosphorylation, could serve as a peripheral blood biomarker, since conformational changes in the PKC enzyme that promote AD pathology are detectable in erythrocytes. [127] Similarly, from the perspective that neuroinflammation promotes neurodegeneration, it may be possible to use elevated serum levels of acute phase proteins and pro-inflammatory cytokines to help gauge the likelihood of progression from MCI to dementia, particularly in the early stages of disease when neuroinflammation is likely to be a relevant biomarker. [128] Although the combined use of serum and CSF to measure AβPP-Aβ peptides, total tau and phosphorylated tau has been proposed for diagnosing and monitoring treatment responses, [129] this approach could be flawed because drug treatments may not produce detectable shifts in serum AβPP-Aβ or tau levels.…”

Section: Cerebrospinal Fluid and Peripheral Blood Diagnostic Biomamentioning

confidence: 99%

Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimerʼs Disease

Monte

2012

Drugs

213

138

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Alzheimer’s disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is fundamentally a metabolic disease that results in progressive impairment in the brain’s capacity to utilize glucose and respond to insulin and insulin-like growth factor (IGF) stimulation. Moreover, the heterogeneous nature of AD is only partly explained by the brain’s propensity to accumulate aberrantly processed, mis-folded and aggregated oligomeric structural proteins, including amyloid-β peptides and hyperphosphorylated tau. Evidence suggests that other factors, including impaired energy metabolism, oxidative stress, neuroinflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into an overarching hypothesis to develop more realistic diagnostic and therapeutic approaches to AD. In this review, the interrelationship between impaired insulin and IGF signalling and amyloid-β pathology is discussed along with potential therapeutic approaches. Impairments in brain insulin/IGF signalling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ. In addition, they promote oxidative stress and deficits in energy metabolism, leading to the activation of pro-AβPP-Aβ-mediated neurodegeneration cascades. Although brain insulin/IGF resistance and deficiency can be induced by primary or secondary disease processes, the soaring rates of peripheral insulin resistance associated with obesity, diabetes mellitus and metabolic syndrome quite likely play major roles in the current AD epidemic. Both clinical and experimental data have linked chronic hyperinsulinaemia to cognitive impairment and neurodegeneration with increased AβPP-Aβ accumulation/reduced clearance in the CNS. Correspondingly, both the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance, although with variable effects on brain AβPP-Aβ load. On the other hand, experimental evidence supports the concept that the toxic effects of AβPP-Aβ can promote insulin resistance. Together, these findings suggest that a positive feedback loop of progressive neurodegeneration can develop whereby insulin resistance drives AβPP-Aβ accumulation, and AβPP-Aβ fibril toxicity drives brain insulin resistance. This phenomenon could explain why measuring AβPP-Aβ levels in cerebrospinal fluid or imaging of the brain has proven to be inadequate as a stand-alone biomarker for diagnosing AD, and why the clinical trial results of anti-AβPP-Aβ monotherapy have been disappointing. Instead, the aggregate data suggest that brain insulin resistance and deficiency must also be therapeutically targeted to halt AD progression or reverse its natural course. The positive therapeutic effects of different treatments that address the role of brain insulin/IGF resistance and deficiency, including the use of intranasal insulin delivery, incretins and insulin sensitizer agents are discussed along with potential benefits of lifestyle change...

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Protein kinase C as a peripheral biomarker for Alzheimer’s disease

Cited by 41 publications

References 41 publications

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimerʼs Disease

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