Neuroinflammation in Alzheimer\u27s Disease and Vascular Cognitive Impairment

It was once believed that the brain was immunologically privileged with no resident or infiltrating immune cells; however, now it is understood that the cells of the brain are capable of a wide range of inflammatory processes and phenotypes. Inflammation in the brain has been implicated in several disease processes such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID); however, the role of inflammation in these two dementias is poorly understood. When we stimulated a pro-inflammatory phenotype with an adeno-associated viral vector in a transgenic mouse model of AD that develops Aβ plaques, we saw a pro-inflammatory response at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in Aβ burden suggesting that anti-inflammatory markers contribute to disease progression. Treatment of astrocytes, microglia, endothelial cells and neurons with high levels of homocysteine, a risk factor for VCID, resulted in a wide range of gene expression changes. Astrocytes showed decreased levels of several potassium channels and aquaporin 4 and increased matrix metalloproteinase 9. Microglia showed an initial pro-inflammatory response that transitioned to an anti-inflammatory phenotype. Endothelial cells showed a disruption in several tight junction proteins and neurons had changes in kinases and phosphatases known to affect tau phosphorylation. Finally, while AD and VCID are the two most common forms of dementia, they are not mutually exclusive and it is estimated that 60% of AD patients also have cerebrovascular pathology contributing to the clinical syndrome. To determine the effect of co-morbid AD and VCID on the effectiveness of therapies that target AD pathologies, we placed APP/PS1 mice on a diet that induces hyperhomocysteinemia and consequently VCID. These mice were then placed on an anti-Aβ immunotherapy. While the co-morbidity mice had a significant reduction in Aβ, there was no cognitive benefit of the immunotherapy in these mice. Interestingly, these co-morbidity mice also had a reduction in inflammatory markers and microglial staining, suggesting a suppressed inflammatory response. From these studies, it is clear that inflammation plays a complex role in AD, VCID and during treatment when both AD and VCID are present

Optimal coupling of waste and concentrated solar for the constant production of electricity over a year

[EN]In this paper a biogas-based Brayton cycle is integrated with a concentrated solar power facility. The gas turbine hot flue gas and the molten salts are used to generate steam for the regenerative Rankine cycle. The process model is solved as a non-linear optimization problem within a multiperiod scheme to decide on the contribution of the energy resources and the operating conditions of the facility to meet a certain demand of power over a year mitigating the absence of solar availability. The steam turbine is responsible for power production while the gas turbine works mainly as a combustion chamber. In the South of Spain an excess of biogas is available during summer yielding a production cost of electricity of 0.17€/kWh with an investment of 380 M€ for a production facility of 25MW. This plant is not yet economic

Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia

Behind only Alzheimer’s disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10–40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, preclinical and clinical data shows it is not. Clinical trials using B vitamin supplementation have shown conflicting results about the benefits of lowering homocysteine and issues have arisen over proper study design within the trials. Studies using cell culture and animal models have proposed several mechanisms for homocysteine-induced cognitive decline, providing other targets for therapeutics. For this review, we will focus on HHcy as a risk factor for VCID, specifically, the different mechanisms proposed for homocysteine-induced cognitive decline and the clinical trials aimed at lowering plasma homocysteine

Western Corn Rootworm Egg Distribution and Adult Emergence under Two Corn Tillage Systems

Under a conventional plowing system, eggs of Diabrotica virgifera LeConte were more uniformly deposited in the top 6 inches of the soil profile than under a reduced strip-tillage system which resulted in heaviest egg deposition in the furrow or ridge. Equal numbers of eggs were deposited in both systems. After corn was planted, more eggs occurred in the seedling zone in conventionally planted corn; in till-plant corn, eggs were removed from the seed row, and eggs concentrated in the furrow were covered with additional soil. Adult emergence was 5–10 days later in till-plant corn than in the conventional tillage system

Influence of gas flow rate on liquid distribution in trickle-beds using perforated plates as liquid distributors

Two wire mesh tomography devices and a liquid collector were used to study the influence of the gas flow rate on liquid distribution when fluids distribution on top of the reactor is ensured by a perforated plate. In opposition to most of the studies realized by other authors, conditions in which the gas has a negative impact in liquid distribution were evidenced. Indeed, the obtained results show that the influence of gas flow rate depends on the quality of the initial distribution, as the gas forces the liquid to "respect" the distribution imposed at the top of the reactor. Finally, a comparison between the two measuring techniques shows the limitations of the liquid collector and the improper conclusions to which its use could lead

Hyperhomocysteinemia-Induced Gene Expression Changes in the Cell Types of the Brain

High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet genes, such as aquaporin 4 and an adenosine triphosphate (ATP)-sensitive inward rectifier potassium channel at 72 hr, as well as an increase in matrix metalloproteinase 9 at 48 hr. Gene changes in microglia indicated a peak in proinflammatory markers at 48 hr followed by a peak in the anti-inflammatory marker, interleukin 1 receptor antagonist, at 72 hr. Endothelial cells had reduced occludin expression at 72 hr, while kinases and phosphatases known to alter tau phosphorylation states were increased in neuronal cells. This suggests that hyperhomocysteinemia induces early proinflammatory changes in microglia and astrocytic changes relevant to their interaction with the vasculature. Overall, the data show how hyperhomocysteinemia could impact Alzheimer’s disease and vascular cognitive impairment and dementia

β-Amyloid Deposition is Shifted to the Vasculature and Memory Impairment is Exacerbated When Hyperhomocysteinemia is Induced in APP/PS1 Transgenic Mice

INTRODUCTION: Vascular dementia is the second most common cause of dementia after Alzheimer\u27s disease (AD). In addition, it is estimated that almost half of all AD patients have significant cerebrovascular disease comorbid with their AD pathology. We hypothesized that cerebrovascular disease significantly impacts AD pathological progression. METHODS: We used a dietary model of cerebrovascular disease that relies on the induction of hyperhomocysteinemia (HHcy). HHcy is a significant clinical risk factor for stroke, cardiovascular disease and type 2 diabetes. In the present study, we induced HHcy in APP/PS1 transgenic mice. RESULTS: While total β-amyloid (Aβ) load is unchanged across groups, Congophilic amyloid deposition was decreased in the parenchyma and significantly increased in the vasculature as cerebral amyloid angiopathy (CAA; vascular amyloid deposition) in HHcy APP/PS1 mice. We also found that HHcy induced more microhemorrhages in the APP/PS1 mice than in the wild-type mice and that it switched the neuroinflammatory phenotype from an M2a biased state to an M1 biased state. Associated with these changes was an induction of the matrix metalloproteinase protein 2 (MMP2) and MMP9 systems. Interestingly, after 6 months of HHcy, the APP/PS1 mice were cognitively worse than wild-type HHcy mice or APP/PS1 mice, indicative of an additive effect of the cerebrovascular pathology and amyloid deposition. CONCLUSIONS: These data show that cerebrovascular disease can significantly impact Aβ distribution in the brain, favoring vascular deposition. We predict that the presence of cerebrovascular disease with AD will have a significant impact on AD progression and the efficacy of therapeutics

Therapeutic Trem2 Activation Ameliorates Amyloid-Beta Deposition and Improves Cognition in the 5XFAD Model of Amyloid Deposition

BACKGROUND: Triggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin. Homozygous TREM2 mutations cause early onset progressive presenile dementia while heterozygous, point mutations triple the risk of Alzheimer\u27s disease (AD). Although human genetic findings support the notion that loss of TREM2 function exacerbates neurodegeneration, it is not clear whether activation of TREM2 in a disease state would result in therapeutic benefits. To determine the viability of TREM2 activation as a therapeutic strategy, we sought to characterize an agonistic Trem2 antibody (AL002a) and test its efficacy and mechanism of action in an aggressive mouse model of amyloid deposition. METHODS: To determine whether agonism of Trem2 results in therapeutic benefits, we designed both intracranial and systemic administration studies. 5XFAD mice in the intracranial administration study were assigned to one of two injection groups: AL002a, a Trem2-agonizing antibody, or MOPC, an isotype-matched control antibody. Mice were then subject to a single bilateral intracranial injection into the frontal cortex and hippocampus and euthanized 72 h later. The tissue from the left hemisphere was histologically examined for amyloid-beta and microglia activation, whereas the tissue from the right hemisphere was used for biochemical analyses. Similarly, mice in the systemic administration study were randomized to one of the aforementioned injection groups and the assigned antibody was administered intraperitoneally once a week for 14 weeks. Mice underwent behavioral assessment between the 12- and 14-week timepoints and were euthanized 24 h after their final injection. The tissue from the left hemisphere was used for histological analyses whereas the tissue from the right hemisphere was used for biochemical analyses. RESULTS: Here, we show that chronic activation of Trem2, in the 5XFAD mouse model of amyloid deposition, leads to reversal of the amyloid-associated gene expression signature, recruitment of microglia to plaques, decreased amyloid deposition, and improvement in spatial learning and novel object recognition memory. CONCLUSIONS: These findings indicate that Trem2 activators may be effective for the treatment of AD and possibly other neurodegenerative disorders

Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia

Behind only Alzheimer’s disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10–40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, preclinical and clinical data shows it is not. Clinical trials using B vitamin supplementation have shown conflicting results about the benefits of lowering homocysteine and issues have arisen over proper study design within the trials. Studies using cell culture and animal models have proposed several mechanisms for homocysteine-induced cognitive decline, providing other targets for therapeutics. For this review, we will focus on HHcy as a risk factor for VCID, specifically, the different mechanisms proposed for homocysteine-induced cognitive decline and the clinical trials aimed at lowering plasma homocysteine

Reduced Efficacy of Anti-A\u3cem\u3eβ\u3c/em\u3e Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer\u27s disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes