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• Review Volume 13, Issue 17 pp 21791-21806

  Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: an adrenergic approach

  Relevance score: 10.823859

  Song Li, Che Wang, Zhen Wang, Jun Tan

  Keywords: Alzheimer's disease, adrenergic receptors, β-amyloid, cerebrovascular, tau

  Published in Aging on September 3, 2021

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  Alzheimer’s disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aβ and tau fails to cover the whole pathological process of AD, and most of the Aβ- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.

• Editorial Volume 10, Issue 11 pp 3048-3049

  Implications of aging in the treatment of complex arrhythmias

  Relevance score: 11.317652

  Sofia Chatzidou, Georgios Georgiopoulos, Christos Kontogiannis

  Keywords: electrical storm, aging, ventricular arrhythmias, β-blockers, adrenergic receptors

  Published in Aging on October 27, 2018

• Research Perspective Volume 2, Issue 4 pp 238-243

  Protein kinase A is a target for aging and the aging heart

  Relevance score: 9.197608

  Linda C Enns, Christina Pettan-Brewer, Warren Ladiges

  Keywords: lifespan extension, obesity resistance, enhanced cardiac function, mouse models of aging, AMPK, beta adrenergic receptors, leptin signaling

  Published in Aging on April 25, 2010

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  PKA is an important mediator of signal transduction downstream of G-protein-coupled receptors and plays a key role in the regulation of metabolism and triglyceride storage. It is a ubiquitous cellular kinase that phosphorylates serine and threonine residues in response to cAMP. PKA consists of two regulatory subunits, RI and RII, that are activated by cAMP to release two catalytic subunits, Cα and Cβ. We have shown that C57/BL6J male mice lacking the regulatory RIIβ subunit have extended lifespan and are resistant to age-related conditions including cardiac decline. In addition to being protected from diet-induced pathologies, PKA Cβ null mutant mice are protected from age-related problems such as weight gain and enlarged livers, as well as cardiac dysfunction and hypertrophy. Several possible mechanisms for the age sparing effects of PKA inhibition are discussed including A kinase anchoring protein signaling, alterations in the β-adrenergic pathway, and activation of AMPK. Since PKA is a major metabolic regulator of gene signaling, the human gene homologs are potential pharmacological targets for age-related conditions including heart disease associated with declining cardiac performance.

  

  The PKA pathway. The PKA pathway is a nutrient sensing pathway. In mammals, nutrients are sensed by a G-protein (GEF) that activates an adenylyl cylase (AC). AC produces cAMP, which binds to the regulatory subunits (R) of the PKA holoenzyme, releasing the catalytic subunits (C), which are then free to enter the nucleus of the cell and activate gene transcription or to interact with other signaling proteins in the cell.

  
  
  

  

  Proposed mechanism for how the PKA Cβ deletion results in resistance to obesity, fatty liver, and heart disease. Activation of AMPK is known to affect different aspects of lipid metabolism, and to play a role in protein synthesis. PKA inhibits activity of AMPK, and we have shown that loss of Cβ results in decreased levels of ChREBP. Our model proposes that disruption of Cβ and concomitant increased AMPK activity leads to a decrease in fatty acid and protein synthesis and an increase in lipolysis and fatty acid oxidation in select tissues. Leptin sensitivity caused by disruption of Cβ may also play a role in the observed increase in AMPK activity in our mutants. A compensatory increase by Cα in the brain also results in an increase in overall energy expenditure.