Abstract
In recent decades, the impairment of cholesterol metabolism in the pathogenesis of Alzheimer’s disease (AD) has been intensively investigated, and it has been recognized to affect amyloid β (Aβ) production and clearance, tau phosphorylation, neuroinflammation and degeneration. In particular, the key role of cholesterol oxidation products, named oxysterols, has emerged. Brain cholesterol metabolism is independent from that of peripheral tissues and it must be preserved in order to guarantee cerebral functions. Among the cells that help maintain brain cholesterol homeostasis, astrocytes play a starring role since they deliver de novo synthesized cholesterol to neurons. In addition, other physiological roles of astrocytes are to modulate synaptic transmission and plasticity and support neurons providing energy. In the AD brain, astrocytes undergo significant morphological and functional changes that contribute to AD onset and development. However, the extent of this contribution and the role played by oxysterols are still unclear. Here we review the current understanding of the physiological role exerted by astrocytes in the brain and their contribution to AD pathogenesis. In particular, we focus on the impact of cholesterol dysmetabolism on astrocyte functions suggesting new potential approaches to develop therapeutic strategies aimed at counteracting AD development.
Highlights
Alzheimer’s disease (AD) is the primary cause of dementia among the elderly, characterized by the gradual loss of memory and cognitive skills needed for day-to-day activities, and it is ranked as the fifth leading cause of death globally [1].AD development is triggered by several events, including oxidative stress, inflammation, amyloid β (Aβ) plaque and neurofibrillary tangle (NFT) formation, causing neurodegeneration
We focus on cholesterol metabolism in the brain and its alterations in AD
glial fibrillary acidic protein (GFAP) immunoreactivity characterizes astrocytes in many central nervous system (CNS) disorders, including AD [4,37,38,39]; it does not necessarily characterize all reactive astrocytes and its up-regulation varies depending on the pathology [3]
Summary
Alzheimer’s disease (AD) is the primary cause of dementia among the elderly, characterized by the gradual loss of memory and cognitive skills needed for day-to-day activities, and it is ranked as the fifth leading cause of death globally [1]. AD development is triggered by several events, including oxidative stress, inflammation, amyloid β (Aβ) plaque and neurofibrillary tangle (NFT) formation, causing neurodegeneration. Astrocytes play a starring role in the brain since they contribute to the maintenance of glutamate, ion and water homeostasis, and they protect from oxidative/nitrosative stress. They modulate synaptic transmission and plasticity and support neurons providing energy substrates and producing cholesterol. In AD brains, different oxysterols of enzymatic and non-enzymatic origin are generated and accumulate in toxic amounts, mainly because of the disruption of BBB integrity [11], playing a crucial role in AD development, by enhancing oxidative stress and inflammation, causing neurodegeneration. We summarize the current knowledge on the impact of cholesterol dysmetabolism on astrocytes, a field that so far remains largely unexplored but that could be relevant for the development of new therapeutic strategies aimed at counteracting AD onset and progression
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