The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here, we show that GLUT1 deficiency in mice overexpressing amyloid β-petpide (Aβ) precursor protein leads to: 1) early cerebral microvascular degeneration, blood flow reductions and dysregulation, and BBB breakdown; and (2) accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function suggesting that GLUT1 may represent a novel therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of bloodderived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1 G93A mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1 G93A mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1 G93A mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.amyotrophic lateral sclerosis | neurodegeneration T he blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) prevent entry of toxic circulating molecules and cells into the central nervous system (CNS) (1). Amyotrophic lateral sclerosis (ALS) is the most prominent adult motor-neuron disorder resulting in progressive motor-neuron loss in the spinal cord, brainstem, and motor cortex (2). Most ALS cases are sporadic (90%) whereas 10% are familial ALS. Over twenty independent studies in postmortem human tissue and cerebrospinal fluid (CSF) sampling from living ALS patients have established that the BBB and BSCB are damaged in familial and sporadic ALS, as reviewed elsewhere (1, 3). This BBB and BSCB disruption has been shown by spinal-cord and/or motor-cortex accumulation of different plasma proteins (e.g., IgG, fibrin, thrombin), erythrocytes, erythrocyte-derived hemoglobin and iron-containing hemosiderin, elevated CSF/serum albumin ratios, and diminished expression or degradation of the BSCB tight-junction proteins (1, 3-5). Deposition of hemoglobin-derived iron within the CNS has also been shown in ALS patients (3, 6, 7). Because human postmortem studies reflect, however, end-stage disease, it has remained unclear as to which stage of disease is enhanced by BSCB disruption. Longitudinal CSF or BSCB imaging studies have yet to be performed in living ALS patients (3) to clarify whether spinal-cord vascular dysfunction contr...

BackgroundChronic stimulant abuse is associated with both impairment in decision making and structural abnormalities in brain gray and white matter. Recent data suggest these structural abnormalities may be related to functional impairment in important behavioral processes.Methodology/Principal FindingsIn 15 cocaine-dependent and 18 control subjects, we examined relationships between decision-making performance on the Iowa Gambling Task (IGT) and white matter integrity as measured by diffusion tensor imaging (DTI). Whole brain voxelwise analyses showed that, relative to controls, the cocaine group had lower fractional anisotropy (FA) and higher mean of the second and third eigenvalues (λ⊥) in frontal and parietal white matter regions and the corpus callosum. Cocaine subjects showed worse performance on the IGT, notably over the last 40 trials. Importantly, FA and λ⊥ values in these regions showed a significant relationship with IGT performance on the last 40 trials.ConclusionsCompromised white matter integrity in cocaine dependence may be related to functional impairments in decision making.

OBJECTIVE-Intravenous insulin infusion rapidly increases plasma insulin, yet glucose disposal occurs at a much slower rate. This delay in insulin's action may be related to the protracted time for insulin to traverse the capillary endothelium. An increased delay may be associated with the development of insulin resistance. The purpose of the present study was to investigate whether bypassing the transendothelial insulin transport step and injecting insulin directly into the interstitial space would moderate the delay in glucose uptake observed with intravenous administration of the hormone. RESEARCH DESIGN AND METHODS-Intramuscular injec-tions of saline (n ϭ 3) or insulin (n ϭ 10) were administered directly into the vastus medialis of anesthetized dogs. Injections of 0.3, 0.5, 0.7, 1.0, and 3.0 units insulin were administered hourly during a basal insulin euglycemic glucose clamp (0.2mU ⅐ minRESULTS-Unlike the saline group, each incremental insulin injection caused interstitial (lymph) insulin to rise within 10 min, indicating rapid diffusion of the hormone within the interstitial matrix. Delay in insulin action was virtually eliminated, indicated by immediate dose-dependent increments in hindlimb glucose uptake. Additionally, bypassing insulin transport by direct injection into muscle revealed a fourfold greater sensitivity to insulin of in vivo muscle tissue than previously reported from intravenous insulin administration.CONCLUSIONS-Our results indicate that the transport of insulin to skeletal muscle is a rate-limiting step for insulin to activate glucose disposal. Based on these results, we speculate that defects in insulin transport across the endothelial layer of skeletal muscle will contribute to insulin resistance. Diabetes 57:828-835, 2008

he APOE4 variant of apolipoprotein E is the strongest genetic risk factor for AD 1 . One and two APOE4 alleles increase risk for AD by approximately 4-and 15-fold, respectively, compared to the more-common APOE3 gene that carries lower risk for AD 1 . Besides accelerating onset and progression of dementia, APOE4 is associated with different brain pathologies. For example, APOE4 accelerates BBB breakdown and degeneration of brain capillary pericytes 2,3 that maintain BBB integrity [4][5][6] and leads to cerebral blood flow (CBF) reduction 7,8 and dysregulation 7,9,10 . APOE4 is toxic to neurons 11 and accelerates tau-mediated neurodegeneration 12 . Additionally, APOE4 slows down amyloid-β (Aβ) clearance 13,14 and accelerates amyloid deposition [14][15][16] , which promotes development of amyloid pathology.Recent studies focused on very early stages in the Alzheimer's continuum in individuals who are cognitively unimpaired or with mild cognitive impairment (MCI) have shown that individuals bearing an APOE4 variant (APOE3/APOE4 or APOE4/APOE4) are distinguished from APOE3 homozygotes by breakdown in the BBB in the hippocampus and medial temporal lobe, regions responsible for memory encoding and cognitive functions 17 . This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with MCI and is independent of Aβ or tau pathology measured in the cerebrospinal fluid or in brain by positron emission tomography 17 . These findings support the growing evidence suggesting that vascular dysfunction, BBB breakdown and vascular disorder contribute to early cognitive impairment and AD [17][18][19][20][21][22][23][24][25][26] . On the other hand, accumulation of Aβ in the brain has also been suggested to occur years before cognitive impairment and continues to increase with disease progression 27 . Although it has been shown that vascular dysfunction contributes to early cognitive impairment in ways that may not be exclusively related to classical AD pathology 17,19,20,26 , the respective contributions of the BBB pathway and vascular disorder versus amyloid-β pathway to advanced disease stage during progression of neurodegenerative disorder and cognitive decline in AD are still poorly understood.To address this question, here we studied vascular dysfunction, Aβ pathology, neuronal dysfunction and behavior in older APOE3 and APOE4 knock-in mice 28 alone and crossed with the 5xFAD line 29 . All mice were derived from the same litters, as previously described 30 . Mice lacking Apoe 3 and/or expressing human APOE4 develop early BBB breakdown 3,[31][32][33] and CBF dysregulation 10 . On the other hand, the 5xFAD line also develops BBB breakdown [34][35][36][37] , CBF reductions 38 and neuron and synaptic loss at a later stage 29,39 , whereas APOE3;5xFAD and APOE4;5xFAD mice (also known as E3FAD and E4FAD lines, respectively 30 ) have comparable Aβ pathology at an older age 40 . These features of the studied models allowed us to interrogate how different pathologies in APOE4 compared to APOE3 mice relat...