Entwined processes in Alzheimer's disease: Brain cellular senescence and Alzheimer's disease pathology

Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases with severe progressive dementia. Amyloid beta (Aβ) deposition and phosphorylated tau accumulation are two typical AD pathologies, which could drive senescence in various types of brain cells. These factors interact to form an entwined vicious cycle, in which each cell could play an irreplaceable role. Thus, it is essential to stress the cause-and-effect relationship in this process and to identify the key factor leading to the vicious cycle. In this narrative review, we discuss (1) how AD pathology induces cellular senescence in different brain cell types; (2) how various accumulated senescent brain cells exacerbate AD pathology; and (3) how cellular senescence and AD pathology are entwined, reinforcing each other through a vicious cycle that accelerates disease progression. We hope to provide insights into the integrated mechanisms linking cellular senescence and AD pathology.

Highlights

• Alzheimer's disease (AD) pathology could mediate senescence-like phenotypes in various brain cells, and each type of cell plays a key role in AD.
• Various senescent brain cells could contribute to AD pathology through diverse mechanisms, with each cell type being indispensable.
• The cause-and-effect relationship between cellular senescence and AD pathology is essential for identifying AD's earlier pathological events and the initiating factors, which still need further exploration.
• An entwined vicious circle exists between brain cellular senescence and AD pathology, in which chronic inflammation, blood–brain barrier damage, neuron loss, and synapse degeneration all play crucial roles.
• Clearance of senescent brain cells could be a promising therapeutic strategy for AD.