Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which is associated with memory deficit and global cognitive decline. Age is the greatest risk factor for AD and, in recent years, it is becoming increasingly appreciated that aging-related neuroinflammation plays a key role in the pathogenesis of AD. The presence of β-amyloid plaques and neurofibrillary tangles are the primary pathological hallmarks of AD; defects which can then activate a cascade of molecular inflammatory pathways in glial cells. Microglia, the resident macrophages in the central nervous system (CNS), are the major triggers of inflammation; a response which is typically intended to prevent further damage to the CNS. However, persistent microglial activation (i.e., neuroinflammation) is toxic to both neurons and glia, which then leads to neurodegeneration. Growing evidence supports a central role for sirtuins in the regulation of neuroinflammation. Sirtuins are NAD+-dependent protein deacetylases that modulate a number of cellular processes associated with inflammation. This review examines the latest findings regarding AD-associated neuroinflammation, mainly focusing on the connections among the microglial molecular pathways of inflammation. Furthermore, we highlight the biology of sirtuins, and their role in neuroinflammation. Suppression of microglial activity through modulation of the sirtuin activity has now become a key area of research, where progress in therapeutic interventions may slow the progression of Alzheimer’s disease.
Highlights
The number of people living with different stages of dementia is growing rapidly, making it a major public health issue all over the world (Rizzi et al, 2014)
In another study it was shown that the enzymes of the mitochondrial redox pathway, including manganese superoxide dismutase (MnSOD), were downregulated in the Sirt3−/− mouse brain, and that the Sirt3 deficiency resulted in mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and assembly of inflammasome in the brain leading to increased production of IL-1β (Tyagi et al, 2018)
Neuroinflammation has being acknowledged as an important pathophysiological feature of neurodegenerative disorders like Alzheimer’s disease
Summary
The number of people living with different stages of dementia is growing rapidly, making it a major public health issue all over the world (Rizzi et al, 2014). Aging is known to be associated with high levels of proinflammatory mediators and increased microglial activity, resulting in chronic inflammation in the brain (i.e., neuroinflammation) and increased bloodbrain barrier (BBB) permeability (Schuitemaker et al, 2012; Elahy et al, 2015). Using a microglia-NSCs co-culture system it has been demonstrated that Aβ induced microglia activation leads to the accumulation of ROS, through the downregulation of Sirt3 and the antioxidant enzyme manganese superoxide dismutase (MnSOD) in NSCs. The overexpression of Sirt3 in NSC provided protection against microglial-derived, cytokine-induced neuronal death (Jiang et al, 2017).
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