Proteostasis disruption and senescence in Alzheimer’s disease pathways to neurodegeneration

Abstract

Alzheimer’s Disease (AD) is a progressive neurological disease associated with behavioral abnormalities, memory loss, and cognitive impairment that cause major causes of dementia in the elderly. The pathogenetic processes cause complex effects on brain function and AD progression. The proper protein homeostasis, or proteostasis, is critical for cell health. AD causes the buildup of misfolded proteins, particularly tau and amyloid-beta, to break down proteostasis, such aggregates are toxic to neurons and play a critical role in AD pathogenesis. The rise of cellular senescence is accompanied by aging, marked by irreversible cell cycle arrest and the release of pro-inflammatory proteins. Senescent cell build-up in the brains of AD patients exacerbates neuroinflammation and neuronal degeneration. These cells senescence-associated secretory phenotype (SASP) also disturbs the brain environment. When proteostasis failure and cellular senescence coalesce, a cycle is generated that compounds each other. While senescent cells contribute to proteostasis breakdown through inflammatory and degradative processes, misfolded proteins induce cellular stress and senescence. The principal aspects of the neurodegenerative processes in AD are the interaction of cellular senescence and proteostasis failure. This review explores the interconnected roles of proteostasis disruption and cellular senescence in the pathways leading to neurodegeneration in AD.