Immunosenescence in Alzheimer's Disease

Researchers here catalog the various mechanisms known to be involved in the development of Alzheimer's disease that occur as a result of the aging of the immune system. The immune system becomes less effective with age, but also constantly overactive. It generates constant and unresolved inflammatory signaling that damages tissue structure and disrupts tissue function. All of the common age-related conditions are accelerated and worsened by the chronic inflammation resulting from the age-damaged immune system.

Alzheimer's disease (AD) is the most common type of dementia characterized by progressive memory loss, visual-spatial impairment, executive dysfunction, and personality and behavioral changes. The pathological features of AD are neuritic plaques, neurofibrillary tangles, neuronal and synaptic loss, and the activation of microglia. Over the past few decades, the amyloid cascade hypothesis has dominated the field of AD research, suggesting that amyloid-β (Aβ) deposition is the central event in AD pathology. However, recent findings have challenged this hypothesis and argue that Aβ protects the brain from infection, and its aggregation promotes microglia-mediated neuroinflammation. The viewpoint that altered immune and inflammatory responses may play the main role in the progression of AD has increasingly been recognized.

In recent years, research is making significant progress and proposes that immunosenescence actively participates in the pathogenesis of AD and mediates inflammatory damage. Microglia are innate immune cells that reside in the brain and play an important role in maintaining homeostasis and immune defense. Microglia undergo significant changes in the aging brain. Morphologically, aged microglia exhibit cytoplasmic hypertrophy and branch reduction. Functionally, senescent microglia show higher proliferative capacity and production of proinflammatory cytokines, but reduced chemotaxis and ability to clear Aβ. Activated and proliferated microglia surround amyloid plaques in the AD brain and participate in the clearance of Aβ. Aβ binds to TLRs, RAGE, and other receptors on the surface of microglia membranes, transducing intracellular signaling pathways, then leading to the synthesis and release of pro-inflammatory factors. In the aging brain, the phagocytic capacity of microglia is weakened, which leads to the accumulation of Aβ. Microglia continue to activate, leading to chronic inflammation, increased oxygen free radicals, mitochondrial damage, and ultimately neuronal death.

Inflammation, a normal repair response, is crucial to combat pathogens and clear dead cells. Once the inflammation is dysregulated, it will cause tissue damage. Inflammaging refers to a state of chronic pro-inflammatory response in the process of aging, which is considered to be a part of immunosenescence. AD is also considered to be a chronic inflammatory disease. The inflammatory response of AD is not limited in the brain, but also exists in peripheral tissues, which is considered to be part of the systemic inflammatory response. The chronic inflammatory state in aging individuals may be associated with long-term chronic microbial infections, which may be a driver of cognitive decline and possibly dementia in the elderly.


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