Neutrophil extracellular traps in amyloid pathology & glymphatic impairment

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Abstract Background Activated neutrophils eject neutrophil extracellular traps (NETs) consisting of web‐like structures of DNA, histones, and granular proteins. Neutrophils traffic into the brain in Alzheimer’s disease (AD) and along with NETs are associated with amyloid beta (Aβ) plaques. However, whether NETs may impair glymphatic clearance of Aβ has never been examined. The glymphatic system is a network of perivascular pathways that provides a pathway for solutes to be cleared from the brain interstitium. Impairment of glymphatic function promotes Aβ plaque deposition. We proposed that NETs may decrease glymphatic exchange by impairing perivascular and interstitial fluid movement, resulting in impaired Aβ clearance. Method 5XFAD mice with amyloid pathology were crossed with Pad4−/− mice lacking the ability to form NETs, generating 5XFAD mice lacking NET formation. Barnes maze, spontaneous alternation Y maze, and open field behavioral tests were performed on 5XFAD+Pad4+/+ and 5XFAD+Pad4−/− mice at 4 months old. The following week, tracer was intracisternally injected into the CSF and dynamic transcranial imaging was performed to measure tracer movement over the cortical surface. Brains were then collected after 45 minutes. Tracer influx was quantified in these brain slices and the tissue was stained for amyloid beta, GFAP, Iba1, and neutrophil markers. Result Pad4 gene deletion in a 5XFAD mouse model of amyloid pathology improved tracer influx, decreased amyloid burden, and improved cognitive function. Conclusion NETs promote glymphatic impairment, amyloid accumulation, and cognitive impairment in a mouse model of amyloid pathology. These studies highlight the important role that neutrophils and NETs play in the pathology of AD and may be a novel therapeutic target.

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