Peer Reviewed Alzheimer's
Posted August 21, 2019
Maiken Nedergaard, M.D., D.M.Sc., University of Rochester
Dr. Maiken Nedergaard
Photo credit: Vincent Sullivan
Photo credit: Vincent Sullivan
Traumatic brain injuries (TBIs) can impair or damage a number of physiological systems in both the grey and white matter and vary in complexity with the severity of the injury. Often, the consequences of the more severe TBIs result in long-term, chronic neurodegeneration. Chronic neurodegeneration is also a key pathological process associated with Alzheimer’s disease (AD) and its related dementias (RDs). While TBI is putatively associated with AD/RDs, the exact mechanisms are vastly uncharacterized. Recently, interest has increased in understanding the role of the glymphatic system in both TBI and AD/RDs. The glymphatic system represents an intricate system of canals and cisterns located within the mammalian brain. One of its intrinsic functions is to clear waste from the brain. Glymphatics function primarily during sleep, hence disruptions in sleep will likely disturb clearance of waste that the brain generates. Sleep disturbances are highly associated with both TBI and AD/RDs. A better understanding of the glymphatic system may help to stabilize damage associated with TBI or the symptoms of AD/RD that can manifest as sleep disruptions.
Dr. Nedergaard and her team at the University of Rochester set out to determine the effect of sleep disruption on glymphatic clearance following TBI. The study included tracking Tau, a protein associated with the tangles often seen in individuals living with AD. Dr. Nedergaard and her team started their experiments with non-penetrating head injury models. Early discoveries have focused on how the brain swells after injury and if the swelling can be mitigated. Dr. Nedergaard found persistent swelling, which she postulated represents an impairment of the glymphatic system since the swelling was evidence of fluid and waste not being cleared from the injured brain. She further explored how the swelling could be controlled by small molecules such as norepinephrine inhibitors. These inhibitors are thought to promote a deeper level of sleep, since norepinephrine is a wakefulness promoter. These inhibitors reduced the swelling, consistent with her research hypothesis. Her team also found a variety of other beneficial effects. Lesion sizes associated with the injuries decreased, as well as behaviors such as anxiety. She is working on demonstrating that proteins such as Tau positively respond to the norepinephrine inhibitor treatment with greater clearance of toxic Tau. Dr. Nedergaard is completing a major experimental challenge, performing her measurements in vivo. Preliminary data are encouraging as her team has cleared several major experimental hurdles. Dr. Nedergaard hopes to accelerate this work further by expanding her arsenal of molecules that affect glymphatic clearance, and by improving the way she and others can image the glymphatic system. Together, this approach may lead to novel ways to understand the enigmatic glymphatic system, and perhaps lead to ways to stabilize the damage associated with neurodegeneration caused by TBI or AD/RDs.
Figure 1: Impairment of the glymphatic system after traumatic brain injury (TBI) can be predicted by transcranial epifluorescent microscopy.
Transcranial macroscopic imaging of fluorescent tracer is equally good for estimation of the peri-vascular flow of CSF tracer. A-C) Cortical impact injury was induced in pre-cannulated C57Bl6 mice using the hit and run the model as described previously by Rene et al., 2013, followed by bovine serum albumin (BSA) conjugated fluorescent tracer injection and transcranial epifluorescent imaging. D-M) Representatives of transcranial in-vivo (D, I), ex-vivo dorsal (E, J), ex-vivo ventral (F, K), and in-vitro brain slice imaging (G, L). Slices labeled by fluorescent conjugated lectin (Lectin 594) and DAPI (blue, pan-nuclear marker) were imaged at high magnification by confocal microscopy (H, M). N-Q) Different imaging approaches were compared by regression analysis; Each of this method seems equally good to predict glymphatic impairment caused by TBI (R2=0.9403, 0.8812, 0.9322, transcranial vs. ex vivo dorsal, transcranial vs. in vitro slices, ex vivo vs. in vitro slices, respectively) except transcranial vs. ex-vivo ventral brain imaging (R2=0.4674). Data (n=10 per group) analyzed using Graph Pad Software, (La Jolla California USA).