Age-Related Neuroinflammation and the Development of Neurodegenerative Conditions

The research community now considers chronic inflammation in brain tissue to be an important aspect of the development of neurodegenerative conditions. Unresolved inflammatory signaling is disruptive of tissue structure and function. With age, a state of chronic inflammation arises due to the presence of senescent cells, the reaction of the innate immune system to debris from stressed cells and metabolic waste such as protein aggregates, persistent viral infection, and a range of other contributing mechanisms. Therapies - such as senolytic treatments to clear senescent cells - that can suppress excess inflammation without affecting the useful, normal inflammatory reaction to injury and infection should slow down many of the manifestations of aging, including the onset of neurodegenerative conditions such as Alzheimer's disease.

Neuroinflammation exists in variety of aging-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), major depressive disorder (MDD), ischemic stroke, spinal cord injury, and schizophrenia. Among the many critical molecules that regulate neuroinflammation, the NLRP3 inflammasome complex was found to play important roles in cellular immune response such as during stress and infection. Recent evidence demonstrates that NLRP3-medicated neuroinflammation is involved in the pathology of neurodegenerative diseases.

Misfolded protein aggregates in neurons are well-known, cellular hallmarks in a variety of neurodegenerative diseases. Misfolded proteins and damaged organelles are degraded by inflammation-related cells such as microglia in the brain. Activated-NLRP3 inflammasome in microglia plays a key role for fighting with misfolded proteins to rescue neurons. Autophagy and ubiquitin-proteasome system in neurons also take part in the degradation or recycling of these mutant aggregates proteins. However, excessive aggregates in neurons impair the autophagy and ubiquitin protein degradation system, leading to activation of NLRP3 inflammasomes in microglia and neuronal death. Microglia activates NLRP3 inflammasomes and releases cytokines in response to toxic protein aggregates in neurodegenerative diseases.

AD is a common, age-dependent neurodegenerative disease which is characterized with the accumulation of amyloid beta (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein aggregates. The Aβ aggregates in brain are considered as a key pathological hallmark of AD. Interestingly, NLRP3 inflammasomes were found in AD patient's brain and animal models. Thus, approaches to degrading protein aggregates by the autophagy system and inhibit the neuroinflammation is a promising direction for the treatment of neurodegenerative diseases characterized by misfolded proteins.