Immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD.
The hallmarks of Alzheimer’s disease (AD) include the presence of beta-amyloid (Aβ) plaques, neurofibrillary tangles, and inflammation. Although the origin and progression of these disease indicators remain poorly understood, a growing body of work implicates systemic immune system activation and neuroinflammatory responses.
Researchers describe an AD mouse model to examine a possible role for plasminogen (PLG), a blood protein whose active form—plasmin (PL)—recruits immune cells known as monocytes and macrophages to regulate the immune response. The authors report that plasminogen depletion, using antisense oligonucleotide (ASO) knockdown, attenuates the brain’s innate immune response and reduces Aβ deposition, decreased glial cell activation in the brain and neuronal damage.
Further, the authors demonstrate that neuroinflammatory activation and Aβ deposition ramp up when plasmin is increased via ASO inhibition of α-2-antiplasmin, the main inhibitor of plasmin. The complex mechanistic interactions between Aβ accumulation, the innate immune system response, and neuroinflammation establish a feedback loop in AD that progressively damages neurons and reduces brain function.
The findings suggest that plasmin plays a central role in the immune system’s response to Aβ formation and may help explain why systemic inflammation is associated with increased risk of AD, according to the authors.
http://www.pnas.org/content/early/2018/09/24/1811172115
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