Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer's Disease

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.

Keywords: Alzheimer’s disease-AD; NF-kB; NLRP3 inflammasome; microglia; neuroinflammantion; sirtuin activators; sirtuins (SIRT).

FIGURE 1

Microglial activity in health and disease. Microglia, the primary innate immune cells in the CNS elicit a protective immune response during an acute brain injury. Microglia are primed with aging. Chronic activation of microglia by Aβ triggers the persistent release of proinflammatory mediators, which can eventually cause neuronal death leading to AD.

FIGURE 2

Microglial inflammatory response in Alzheimer’s disease. Microglia detect the presence of Aβ by a number of cell surface receptors, which trigger the microglial inflammatory response through activation of the proinflammatory transcription factor NF-κB and NLRP3 inflammasome. Sirtuins, particularly Sirt1-3 inhibit neuroinflammation in AD possibly by suppressing NF-κB and NLRP3 inflammasome activity.