MRI visualization of activated monocytes accumulation in the CNS of P301S tau mice by targeted nanoparticle technology: An approach to MRI molecular imaging of neuroinflammation

Abstract

AbstractBackgroundChronic neuroinflammation plays a critical role in the pathophysiology of Alzheimer’s disease (AD) and related dementias. The CNS is immune privileged with restricted peripheral leukocyte traffic under normal physiological conditions. Neuroinflammation in disease brains is often accompanied by BBB compromise and increase CNS infiltration by activated peripheral monocytes/macrophages. Part of the inflammatory response in these cells is upregulation of the integrin, very late antigen‐4 (VLA‐4) and present a valuable target for detection and treatment of neuroinflammation.MethodIn vivo MRI scans were performed on 9 to 12 months old P301S mice on a 1 Tesla small animal MR scanner using a 2D fast spin echo inversion recovery (FSE‐IR) scan protocol that approximates a fluid‐attenuated inversion recovery (FLAIR) sequence (scan parameters: TR = 6500 ms, TE = 80 ms, TI = 2000 ms, slice thickness = 2.4 mm, matrix = 192x192, FOV = 30 mm, slices = 6, NEX = 6). Mice were pre‐scanned to obtain a baseline image and then injected with Rhodamine‐labeled VLA‐4 targeted nanoparticles bearing a T1 MR relaxive payload. Four days post‐contrast injections, they were rescanned and then euthanized and brain tissue harvested for ex‐vivo immunohistochemical analysis by confocal microscopy. Test animals included transgenic mice injected with the targeted agent (n = 6). Controls included transgenic mice injected with a non‐targeted agent (n = 6) and wild‐type age‐matched litter mates injected with the targeted agent (n = 6).ResultMR images 4 days post contrast administration showed on average, higher accumulation of the contrast agent in the brains of the test mice compared to moderate to low levels of accumulation in the control mice. The in vivo MR data is validated by ex‐vivo histology results which also showed higher Rhodamine signal intensity in brain disuse sections from the test mice compared to controls. The high accumulation in the test mice is attributed to both active and active particle uptake mechanisms while only passive mechanisms are possible in the controls.ConclusionVLA‐4 targeted MRI sensitive nanoparticles label activated monocytes/macrophages in P301S mice CNS, enabling noninvasive detection of neuroinflammatory activity and highlighting a potentially novel approach to imaging neuroinflammation in AD.