Extracellular aggregation of the amyloid-β (Aβ) peptide into toxic multimers is a key event in Alzheimer's disease (AD) pathogenesis. Aβ aggregation is concentration-dependent, with higher ...concentrations of Aβ much more likely to form toxic species. The processes that regulate extracellular levels of Aβ therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Aβ production through both presynaptic and postsynaptic mechanisms. AMPA receptors (AMPA-Rs), as the most abundant ionotropic glutamate receptors, have the potential to greatly impact Aβ levels.
In order to study the role of AMPA-Rs in Aβ regulation, we used in vivo microdialysis in an APP/PS1 mouse model to simultaneously deliver AMPA and other treatments while collecting Aβ from the interstitial fluid (ISF). Changes in Aβ production and clearance along with inflammation were assessed using biochemical approaches. IL-6 deficient mice were utilized to test the role of IL-6 signaling in AMPA-R-mediated regulation of Aβ levels.
We found that AMPA-R activation decreases in ISF Aβ levels in a dose-dependent manner. Moreover, the effect of AMPA treatment involves three distinct pathways. Steady-state activity of AMPA-Rs normally promotes higher ISF Aβ. Evoked AMPA-R activity, however, decreases Aβ levels by both stimulating glutamatergic transmission and activating downstream NMDA receptor (NMDA-R) signaling and, with extended AMPA treatment, acting independently of NMDA-Rs. Surprisingly, we found this latter, direct AMPA pathway of Aβ regulation increases Aβ clearance, while Aβ production appears to be largely unaffected. Furthermore, the AMPA-dependent decrease is not observed in IL-6 deficient mice, indicating a role for IL-6 signaling in AMPA-R-mediated Aβ clearance.
Though basal levels of AMPA-R activity promote higher levels of ISF Aβ, evoked AMPA-R signaling decreases Aβ through both NMDA-R-dependent and -independent pathways. We find that evoked AMPA-R signaling increases clearance of extracellular Aβ, at least in part through enhanced IL-6 signaling. These data emphasize that Aβ regulation by synaptic activity involves a number of independent pathways that together determine extracellular Aβ levels. Understanding how these pathways maintain Aβ levels prior to AD pathology may provide insights into disease pathogenesis.
Bad Ac-etylated Tau Hettinger, Jane C.; Cirrito, John R.
Neuron,
04/2016, Letnik:
90, Številka:
2
Journal Article
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By using a tau construct with two mimicked acetylation sites as identified in AD brains, Tracy et al. (2016) found that acetylated tau promotes synaptic dysfunction through disruption of postsynaptic ...KIBRA signaling pathways, actin dynamics, and AMPA receptor trafficking.
By using a tau construct with two mimicked acetylation sites as identified in AD brains, Tracy et al. found that acetylated tau promotes synaptic dysfunction through disruption of postsynaptic KIBRA signaling pathways, actin dynamics, and AMPA receptor trafficking.
Amyloid‐β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ ...generation, we postulated that 5HT2A‐Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real‐time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A‐R knock‐out mice. The Aβ‐lowering effects of Pimavanserin were blocked by extracellular‐regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA‐approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease‐modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease.
Read the Editorial Highlight for this article on page 560.
(A) Pimavanserin (Pim) reduces activity at 5HT2A‐Rs which indirectly leads to activation of NMDARs (B). Calcium influx through NMDARs causes phosphorylation and activation of the extracellular regulated kinase (ERK) (C). ERK likely directly phosphorylates an α‐secretase protease which increases its enzymatic activity (D). An increase in non‐amyloidogenic processing of APP suppresses Aβ generation (E). Acute Pimavanserin causes a sustained 40% decrease in brain interstitial fluid Aβ levels of mice, whereas a chronic administration to aged APP/PS1 mice that already contain Aβ pathology causes a 30% decrease in Aβ plaques as well as improves several behavioral measures.
This article has an Editorial Highlight, see https://doi.org/10.1111/jnc.15269
Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of ...Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.
Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ ...generation, we postulated that 5HT
-Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT
inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT
-R knock-out mice. The Aβ-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.
Physical activity and stress are both environmental modifiers of Alzheimer's disease (AD) risk. Animal studies of physical activity in AD models have largely reported positive results, however ...benefits are not always observed in either cognitive or pathological outcomes and inconsistencies among findings remain. Studies using forced exercise may increase stress and mitigate some of the benefit of physical activity in AD models, while voluntary exercise regimens may not achieve optimal intensity to provide robust benefit. We evaluated the findings of studies of voluntary and forced exercise regimens in AD mouse models to determine the influence of stress, or the intensity of exercise needed to outweigh the negative effects of stress on AD measures. In addition, we show that chronic physical activity in a mouse model of AD can prevent the effects of acute restraint stress on Aβ levels in the hippocampus. Stress and physical activity have many overlapping and divergent effects on the body and some of the possible mechanisms through which physical activity may protect against stress-induced risk factors for AD are discussed. While the physiological effects of acute stress and acute exercise overlap, chronic effects of physical activity appear to directly oppose the effects of chronic stress on risk factors for AD. Further study is needed to identify optimal parameters for intensity, duration and frequency of physical activity to counterbalance effects of stress on the development and progression of AD.
Ischemic preconditioning is a phenomenon in which low-level stressful stimuli upregulate endogenous defensive programs, resulting in subsequent resistance to otherwise lethal injuries. We previously ...observed that signal transduction systems typically associated with neurodegeneration such as caspase activation are requisite events for the expression of tolerance and induction of HSP70. In this work, we sought to determine the extent and duration of oxidative and energetic dysfunction as well as the role of effector kinases on metabolic function in preconditioned cells. Using an in vitro neuronal culture model, we observed a robust increase in Raf and p66(Shc) activation within 1 h of preconditioning. Total ATP content decreased by 25% 3 h after preconditioning but returned to baseline by 24 h. Use of a free radical spin trap or p66(shc) inhibitor increased ATP content whereas a Raf inhibitor had no effect. Phosphorylated p66(shc) rapidly relocalized to the mitochondria and in the absence of activated p66(shc), autophagic processing increased. The constitutively expressed chaperone HSC70 relocalized to autophagosomes. Preconditioned cells experience significant total oxidative stress measured by F(2)-isoprostanes and neuronal stress evaluated by F(4)-neuroprostane measurement. Neuroprostane levels were enhanced in the presence of Shc inhibitors. Finally, we found that inhibiting either p66(shc) or Raf blocked neuroprotection afforded by preconditioning as well as upregulation of HSP70, suggesting both kinases are critical for preconditioning but function in fundamentally different ways. This is the first work to demonstrate the essential role of p66(shc) in mediating requisite mitochondrial and energetic compensation after preconditioning and suggests a mechanism by which protein and organelle damage mediated by ROS can increase HSP70.
Stroke is the leading cause of adult disability in the U.S. and is now recognized as a global epidemic. There are currently no FDA-approved drugs to block the cell death that results from oxygen and ...glucose deprivation. This void in clinical medicine has sparked an intense interest in understanding endogenous cellular protective pathways that might be exploited for therapeutic development. The work highlighted here describes the critical role between redox tone and energetic stress signaling in mediating mitophagy and determining neuronal cell fate following acute oxygen glucose deprivation.
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