IntroductionCurrent therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Histone deacetylase 6 (HDAC6) modulates tubulin acetylation and has been implicated as an attractive target. HDAC6 is also elevated in postmortem tissue samples from patients. However, HDAC6 inhibitors have had limited success preclinically due to low blood-brain barrier penetration.MethodWe investigated a specific, potent HDAC6 inhibitor (ACY-738) in a mouse model of AD. We determined the effects of ACY-738 treatment on axonal transport, behavior, and pathology in amyloid precursor protein/presenilin 1 mice.ResultsWe demonstrated improvements in in vivo axonal transport in two treatment groups as a result of ACY-738 brain levels. We also demonstrated recovery of short-term learning and memory deficits, hyperactivity, and modifications of tau and tubulin.DiscussionOur findings implicate specific, targeted HDAC6 inhibitors as potential therapeutics and demonstrate that further investigations are warranted into effects of HDAC6 inhibitors in AD.

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In many human diseases, the presence of inflammation is associated with an increase in the level of reactive oxygen species (ROS). The resulting state of oxidative stress is highly detrimental and can initiate a cascade of events that ultimately lead to cell death. Thus, many therapeutic attempts have been focused on either modulating the immune system to lower inflammation or reducing the damaging caused by ROS. Berlin et al. reported the development of a novel nanoantioxidant known as poly(ethylene glycol)‐functionalized‐hydrophilic carbon clusters (PEG‐HCCs). They showed that PEG‐HCCs could be targeted to cancer cells, utilized as a drug delivery vector, and can even be visualized ex vivo. Our work here furthers this work and characterizes Gd‐DTPA conjugated PEG‐HCCs and explores the potential for in vivo tracking of T cells in live mice. We utilized a mouse model of delayed‐type hypersensitivity (DTH) to assess the immunomodulatory effects of PEG‐HCCs. The T 1‐agent Gd‐DTPA was then conjugated to the PEG‐HCCs and T 1 measurements, and T 1‐weighted MRI of the modified PEG‐HCCs was done to assess their relaxivity. We then assessed if PEG‐HCCs could be visualized both ex vivo and in vivo within the mouse lymph node and spleen. Mice treated with PEG‐HCCs showed significant improvements in the DTH assay as compared to the vehicle (saline)‐treated control. Flow cytometry demonstrated that splenic T cells are capable of internalizing PEG‐HCCs whereas fluorescent immunohistochemistry showed that PEG‐HCCs are detectable within the cortex of lymph nodes. Finally, our nanoantioxidants can be visualized in vivo within the lymph nodes and spleen of a mouse after addition of the Gd‐DTPA. PEG‐HCCs are internalized by T cells in the spleen and can reduce inflammation by suppression of a recall immune response. PEG‐HCCs can be modified to allow for both in vitro and in vivo visualization using MRI. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

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