Endothelial Dysfunction and Pre-Existing Cognitive Disorders in Stroke Patients.

BACKGROUND: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. OBJECTIVE: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. METHODS: Patients originated from the prospective STROKDEM study. The baseline cognitive state, assessed using the IQ-CODE, and risk factors for stroke were recorded at inclusion. Patients with an IQ-CODE score >64 were excluded. Endothelial function was determined 72 h after stroke symptom onset by non-invasive digital measurement of endothelium-dependent flow-mediated dilation and calculation of the reactive hyperemia index (RHI). RHI ≤ 1.67 indicated endothelial dysfunction. Different biomarkers of endothelial dysfunction were analysed in blood or plasma. All patients underwent MRI 72 h after stroke symptom onset. RESULTS: A total of 86 patients were included (52 males; mean age 63.5 ± 11.5 years). Patients with abnormal RHI have hypertension or antihypertensive treatment more often. The baseline IQ-CODE was abnormal in 33 (38.4%) patients, indicating a pre-existing cognitive problem. Baseline IQ-CODE > 48 was observed in 15 patients (28.3%) with normal RHI and in 18 patients (54.6%) with abnormal RHI (p = 0.016). The RHI median was significantly lower in patients with abnormal IQ-CODE. Abnormal RHI was associated with a significantly higher median FAZEKAS score (2.5 vs. 2; p = 0.008), a significantly higher frequency of periventricular lesions (p = 0.015), more white matter lesions (p = 0.007) and a significantly higher cerebral atrophy score (p < 0.001) on MRI. Vascular biomarkers significantly associated with abnormal RHI were MCP-1 (p = 0.009), MIP_1a (p = 0.042), and homocysteinemia (p < 0.05). CONCLUSIONS: A vascular mechanism may be responsible for cognitive problems pre-existing stroke. The measurement of endothelial dysfunction after stroke could become an important element of follow-up, providing an indication of the functional and cognitive prognosis of stroke patients.

Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia.

OBJECTIVE: Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism. METHODS AND RESULTS: Liver-specific insulin receptor-deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces apoCIII transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element-binding protein and hepatocyte nuclear factor-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. CONCLUSIONS: Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.

Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model.

Alzheimer's disease (AD) is the leading cause of dementia. While impaired glucose homeostasis has been shown to increase AD risk and pathological loss of tau function, the latter has been suggested to contribute to the emergence of the glucose homeostasis alterations observed in AD patients. However, the links between tau impairments and glucose homeostasis, remain unclear. In this context, the present study aimed at investigating the metabolic phenotype of a new tau knock-in (KI) mouse model, expressing, at a physiological level, a human tau protein bearing the P301L mutation under the control of the endogenous mouse Mapt promoter. Metabolic investigations revealed that, while under chow diet tau KI mice do not exhibit significant metabolic impairments, male but not female tau KI animals under High-Fat Diet (HFD) exhibited higher insulinemia as well as glucose intolerance as compared to control littermates. Using immunofluorescence, tau protein was found colocalized with insulin in the ß cells of pancreatic islets in both mouse (WT, KI) and human pancreas. Isolated islets from tau KI and tau knock-out mice exhibited impaired glucose-stimulated insulin secretion (GSIS), an effect recapitulated in the mouse pancreatic ß-cell line (MIN6) following tau knock-down. Altogether, our data indicate that loss of tau function in tau KI mice and, particularly, dysfunction of pancreatic ß cells might promote glucose homeostasis impairments and contribute to metabolic changes observed in AD.

Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology.

Tau pathology is encountered in many neurodegenerative disorders known as tauopathies, including Alzheimer's disease. Physical activity is a lifestyle factor affecting processes crucial for memory and synaptic plasticity. Whether long-term voluntary exercise has an impact on Tau pathology and its pathophysiological consequences is currently unknown. To address this question, we investigated the effects of long-term voluntary exercise in the THY-Tau22 transgenic model of Alzheimer's disease-like Tau pathology, characterized by the progressive development of Tau pathology, cholinergic alterations and subsequent memory impairments. Three-month-old THY-Tau22 mice and wild-type littermates were assigned to standard housing or housing supplemented with a running wheel. After 9 months of exercise, mice were evaluated for memory performance and examined for hippocampal Tau pathology, cholinergic defects, inflammation and genes related to cholesterol metabolism. Exercise prevented memory alterations in THY-Tau22 mice. This was accompanied by a decrease in hippocampal Tau pathology and a prevention of the loss of expression of choline acetyltransferase within the medial septum. Whereas the expression of most cholesterol-related genes remained unchanged in the hippocampus of running THY-Tau22 mice, we observed a significant upregulation in mRNA levels of NPC1 and NPC2, genes involved in cholesterol trafficking from the lysosomes. Our data support the view that long-term voluntary physical exercise is an effective strategy capable of mitigating Tau pathology and its pathophysiological consequences.

Aß1-40 and Aß1-42 Plasmatic Levels In Stroke: Influence of Pre-Existing Cognitive Status and Stroke Characteristics.

Many stroke patients have pre-existing cognitive impairment. Plasma amyloid ß peptides (Aß) - possible biomarkers of Alzheimer's pathology - induce vascular dysfunction. Our objective was to evaluate factors influencing plasma Aß1-40 and Aß1-42 peptides in a cohort of stroke patients. In the Biostroke study (ClinicalTrials.gov Identifier: NCT00763217), we collected vascular risk factors, neuroimaging features and biological tests including Aß1-40 and Aß1-42. We used the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to systematically assess the pre-existing cognitive status. Of 403 patients (371 ischemia), 25 met criteria for pre-existing dementia, 142 for pre-existing cognitive decline-no-dementia, and 236 had no PCoI. Aß1-42 was independently associated with PCoI (odds ratio 0.973; 95% confidence interval: 0.950-0.996; p=0.024). Factors associated with plasma Aß1- 40 were age, smoking and diabetes mellitus. After exclusion of hemorrhagic strokes, the results remained unchanged, but blood samples taken less than 12 hours after onset were associated with lower plasma Aß1-40. Our results support a dissociated response of the 2 plasma Aß peptides in stroke patients, plasma Aß1-40 being involved in vascular aspects whereas Aß1-42 might be involved in neurodegenerative processes.

NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model.

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.