Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic ...vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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KISLJ, NUK, SBMB, UL, UM, UPUK
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Laboratory animals are routinely surgically instrumented for experimentation and housed at ambient temperatures ranging from 20°C – 26°C during recovery per recommended guidelines. ...However, rats typically prefer ambient temperatures (Tamb) of ~27 °C (Brown and Le 2011). Rats are often housed at normal room temperature (~22 °C). While this is comfortable to those maintaining them, it may lead to a cold thermal stress for the rats. It is hypothesized that housing rats at ambient temperatures away from their preferred Tamb could lead to a thermal stress which adversely affects surgical recovery. To address this, adult rats (220g–320g) were surgically instrumented with a radiotelemetry probe (DSI), which allows non‐invasive measurement of core temperature (Tc). Also, a cannula (21ga) was inserted into the brainstem to allow microinjection of drugs as part of a separate project. For ≥1 week of recovery, the rats were housed at either 21°C, 24°C, 27°C (control), 30°C, or 33°C Tamb while Tc, food and water intake, and body weight changes were measured. Rats housed at 21°C and 24°C struggled to recover a normal Tc initially. This delayed the onset of normal circadian cycling in the 21°C group. Rats housed at 33°C recovered quickly and then maintained a slightly elevated Tc compared to control (27°C). The 30°C and 33°C groups would reestablish Tc circadian rhythms faster than the control, but the 33°C would struggle to maintain that rhythm near the end of the recovery week. The return of body weight to pre‐surgical levels was delayed in rats housed at the warm Tamb (30°C & 33°C) or the very low Tamb (21°C). The effect of Tamb on daily food and water intake after surgery was not remarkable except for on the 5th day of recovery in the 30°C and 33°C groups when water intake increased. The 21°C and 24°C increased food intake after the 4
th
day in comparison to the control (27°C). These data suggest that rats maintained at 27°C recovered from surgical stress more readily. These rats returned to pre‐surgical body weight quicker and demonstrated a normal thermoregulatory circadian rhythm earlier than the cold (21 or 24°C) rats. Rats housed at ≥ 30°C may have been exposed to a heat stress which affected weight gain and surgical recovery initially but impaired normal circadian cycling later in the week. Rats housed at 21°C may have been cold stressed which also affected weight gain and thermoregulatory recovery. It is suggested that rats be maintained at their preferred Tamb of 27 °C during the week following surgery to minimize thermal stress and thereby facilitate recovery. This reduction in stress facilitates the return to a normal physiologic state and consequently enables more reliable data collection from these animals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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