LSR
Lipolysis-stimulated lipoprotein receptor [LISCH]
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The regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer's disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multimeric protein complex that has multiple isoforms including α and α', which are seen as a doublet at 68 kDa, and β at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr /- mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypothalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life.
MeSH Terms
- Aging
- Animals
- Brain
- Cholesterol
- Homeostasis
- Humans
- Lipolysis
- Male
- Mice
- Mice, Inbred C57BL
- Neuroglia
- Neurons
- RNA, Messenger
- Receptors, Lipoprotein
- Tissue Distribution
- Transcriptome
Hippocampal atrophy is one of the main hallmarks of Alzheimer's disease (AD). However, there is still controversy about whether this sign is a robust finding during the early stages of the disease, such as in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Considering this background, we proposed a new marker for assessing hippocampal atrophy: the local surface roughness (LSR). We tested this marker in a sample of 307 subjects (normal control (NC) = 70, SCD = 87, MCI = 137, AD = 13). In addition, 97 patients with MCI were followed-up over a 3-year period and classified as stable MCI (sMCI) (n = 61) or progressive MCI (pMCI) (n = 36). We did not find significant differences using traditional markers, such as normalized hippocampal volumes (NHV), between the NC and SCD groups or between the sMCI and pMCI groups. However, with LSR we found significant differences between the sMCI and pMCI groups and a better ability to discriminate between NC and SCD. The classification accuracy of the LSR for NC and SCD was 68.2%, while NHV had a 57.2% accuracy. In addition, the classification accuracy of the LSR for sMCI and pMCI was 74.3%, and NHV had a 68.3% accuracy. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on hippocampal markers and conversion times. The LSR marker showed better prediction of conversion to AD than NHV. These results suggest the relevance of considering the LSR as a new hippocampal marker for the AD continuum.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Algorithms
- Alzheimer Disease
- Biomarkers
- Cognitive Dysfunction
- Disease Progression
- Educational Status
- Female
- Follow-Up Studies
- Hippocampus
- Humans
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Reproducibility of Results
- Sex Characteristics
Keywords
- Alzheimer's disease continuum
- hippocampal biomarkers
- hippocampal segmentation
- local surface roughness
- progression to AD
Mouse models are increasingly employed in the comprehension of cardiovascular disease. Wave Intensity Analysis (WIA) can provide information about the interaction between the vascular and the cardiac system. We investigate age-associated changes in WIA-derived parameters in mice and correlate them with biomarkers of cardiac function. Sixteen wild-type male mice were imaged with high-resolution ultrasound (US) at 8 weeks (T ) and 25 weeks (T ) of age. Carotid pulse wave velocity (PWV) was calculated from US images using the diameter-velocity loop and employed to evaluate WIA. Amplitudes of the first (W ) and the second (W ) local maxima, local minimum (W ) and the reflection index (RI = W /W ) were assessed. Cardiac output (CO), ejection fraction (EF), fractional shortening (FS) and stroke volume (SV) were evaluated; longitudinal, radial and circumferential strain and strain rate values (LS, LSR, RS, RSR, CS, CSR) were obtained through strain analysis. W (T : 4.42e-07 ± 2.32e-07 m /s; T : 2.21e-07 ± 9.77 m /s), W (T : 2.45e-08 ± 9.63e-09 m /s; T : 1.78e-08 ± 7.82 m /s), W (T : -8.75e-08 ± 5.45e-08 m /s; T : -4.28e-08 ± 2.22e-08 m /s), CO (T : 19.27 ± 4.33 ml/min; T : 16.71 ± 2.88 ml/min), LS (T : 17.55 ± 3.67%; T : 15.05 ± 2.89%), LSR (T : 6.02 ± 1.39 s ; T : 5.02 ± 1.25 s ), CS (T : 27.5 ± 5.18%; T : 22.66 ± 3.09%) and CSR (T : 10.03 ± 2.55 s ; T : 7.50 ± 1.84 s ) significantly reduced with age. W was significantly correlated with CO (R = 0.58), EF (R = 0.72), LS (R = 0.65), LSR (R = 0.89), CS (R = 0.61), CSR (R = 0.70) at T ; correlations were lost at T . The decrease in W and W suggests a cardiac performance reduction, while that in W , considering unchanged RI, might indicate a wave energy decrease. The loss of correlation between WIA-derived and cardiac parameters might reflect an alteration in cardiovascular interaction.
MeSH Terms
- Age Factors
- Animals
- Blood Flow Velocity
- Carotid Arteries
- Heart
- Male
- Mice
- Mice, Inbred C57BL
- Pulse Wave Analysis
- Stroke Volume
- Ultrasonography, Doppler
Keywords
- Aging
- Cardiovascular interaction
- Mouse models
- Wave intensity analysis
It is unknown if diabetes-related reductions in local skin blood flow (SkBF) and sweating (LSR) measured during passive heat stress translate into greater heat storage during exercise in the heat in individuals with type 2 diabetes (T2D) compared with nondiabetic control (CON) subjects. This study aimed to examine the effects of T2D on whole-body heat exchange during exercise in the heat. Ten adults (6 males and 4 females) with T2D and 10 adults (6 males and 4 females) without diabetes matched for age, sex, body surface area, and body surface area and aerobic fitness cycled continuously for 60 min at a fixed rate of metabolic heat production (∼370 W) in a whole-body direct calorimeter (30°C and 20% relative humidity). Upper back LSR, forearm SkBF, rectal temperature, and heart rate were measured continuously. Whole-body heat loss and changes in body heat content (ΔHb) were determined using simultaneous direct whole-body and indirect calorimetry. Whole-body heat loss was significantly attenuated from 15 min throughout the remaining exercise with the differences becoming more pronounced over time for T2D relative to CON (P = 0.004). This resulted in a significantly greater ΔHb in T2D (367 ± 35; CON, 238 ± 25 kJ, P = 0.002). No differences were measured during recovery (T2D, -79 ± 23; CON, -132 ± 23 kJ, P = 0.083). By the end of the 60-min recovery, the T2D group lost only 21% (79 kJ) of the total heat gained during exercise, whereas their nondiabetic counterparts lost in excess of 55% (131 kJ). No difference were observed in LSR, SkBF, rectal temperature or heart rate during exercise. Similarly, no differences were measured during recovery with the exception that heart rate was elevated in the T2D group relative to CON (p=0.004). Older adults with T2D have a reduced capacity to dissipate heat during exercise, resulting in a greater heat storage and therefore level of thermal strain.
MeSH Terms
- Aging
- Bicycling
- Body Temperature
- Body Temperature Regulation
- Case-Control Studies
- Diabetes Mellitus, Type 2
- Exercise Test
- Female
- Heart Rate
- Hot Temperature
- Humans
- Male
- Middle Aged
- Physical Exertion
- Regional Blood Flow
- Skin
- Sweating