Comprehensive Overview of Alzheimer’s Disease Neurodegeneration, from Amyloid-β to Neuroinflammatory Modulation

Alzheimer’s disease (AD) constitutes a major health threat to elder people. Despite the great advances achieved regarding our knowledge of the disease, we are far to successfully treat this pathology. Molecular alterations, immune/inflammatory response, and cell death are some of the processes involved during the pathology. Moreover, AD affects the whole brain. In this regard, we must not only consider the health status of neurons, of course, but also pay attention to the status of the glial cells and additional surrounding structures, such as the blood-brain barrier (BBB). Several groups have demonstrated how the molecular alterations occurring during AD alter neurons, glial, and endothelial cells. This situation has become so relevant that different groups are currently working to unveil the blank spaces in our understanding about the co-involvement of these elements in AD. Based in our experience, we believe that this kind of approach will lead to the design and development of more comprehensive therapeutical interventions. The present chapter summarizes the relevant aspects of state of the art regarding AD, from its molecular genesis to the recent advances in neuroinflammatory modulation, including nuclear receptors (NR), such as peroxisome proliferator-activated receptors (PPARs), and the Wnt pathway involved in the AD neurodegeneration

Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades in Alzheimer’s and Parkinson’s Diseases

Sterile inflammatory response constitutes a main event in several neurodegenerative disorders. Alzheimer’s disease (AD) and Parkinson’s disease (PD), the leading degenerative pathologies of the central nervous system worldwide, exhibit a strong inflammatory component. Microglial and astrocytic reactivity, increased levels of inflammatory mediators, neuronal damage, and death are part of the pathological scenario leading to the progressive failure of the brain neuronal network. In this regard, the link between the toll-like receptors (TLRs)-mediated inflammatory cascade and the molecular hallmarks of AD and PD have been demonstrated elsewhere. Moreover, the long-lasting exposure to the inflammatory environment is considered one of the key elements leading to the establishment and progression of these pathologies. Accordingly, the modulation of the inflammatory response has emerged as a main target of new therapeutic approaches to fight these diseases. In this regard, and based on our previous works on this subject, we describe the pathological profile of both pathologies but in the inflammatory context. Thus, in the present chapter, we will introduce the main aspects of both diseases and how they interplay with the TLR-mediated response. We believe that this chapter should provide a concise overview of the roles of TLRs in the inflammatory cascades triggered during AD and PD pathophysiology

Molecular Basis of Neurodegeneration: Lessons from Alzheimer’s and Parkinson’s Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) constitute the main causes of dementia worldwide and the major health threats to elderly people. Moreover, with the ageing of the global population, neurodegenerative disorders, such as AD and PD, constitute a major public health issue. Regrettably, significant advances regarding the molecular aspects of these diseases have not yet been translated into real improvements in AD/PD therapeutics. In this regard, both AD and PD are highly complex and involve critical molecular events governing the establishment and progression of each disease. Moreover, molecular alterations trigger pathophysiological cascades involving the immune/inflammatory response, oxidative stress, and mitochondrial dysfunction, among others, ultimately leading to neuronal death. Similarly, these alterations also affect glial cells and brain vasculature, which contribute directly to the progression of these disorders. Accordingly, the present paper aims to summarise the main molecular elements related to AD and PD as well as the pathophysiological implications of such alterations to improve our understanding of the cellular and molecular responses observed during neurodegeneration. We believe that providing a more comprehensive view of the pathophysiological cascade, including neurons and glial cells, might prompt researchers to widen neurodegenerative disorder research and therapeutic approaches

Study of an advanced General Aviation Turbine Engine (GATE)

The best technology program for a small, economically viable gas turbine engine applicable to the general aviation helicopter and aircraft market for 1985-1990 was studied. Turboshaft and turboprop engines in the 112 to 746 kW (150 to 1000 hp) range and turbofan engines up to 6672 N (1500 lbf) thrust were considered. A good market for new turbine engines was predicted for 1988 providing aircraft are designed to capitalize on the advantages of the turbine engine. Parametric engine families were defined in terms of design and off-design performance, mass, and cost. These were evaluated in aircraft design missions selected to represent important market segments for fixed and rotary-wing applications. Payoff parameters influenced by engine cycle and configuration changes were aircraft gross mass, acquisition cost, total cost of ownership, and cash flow. Significant advantage over a current technology, small gas turbine engines was found especially in cost of ownership and fuel economy for airframes incorporating an air-cooled high-pressure ratio engine. A power class of 373 kW (500 hp) was recommended as the next frontier for technology advance where large improvements in fuel economy and engine mass appear possible through component research and development

Potentially inappropriate medication use: the Beers' Criteria used among older adults with depressive symptoms

INTRODUCTION: The ageing population means prescribing for chronic illnesses in older people is expected to rise. Comorbidities and compromised organ function may complicate prescribing and increase medication-related risks. Comorbid depression in older people is highly prevalent and complicates medication prescribing decisions. AIM: To determine the prevalence of potentially inappropriate medication use in a community-dwelling population of older adults with depressive symptoms. METHODS: The medications of 191 community-dwelling older people selected because of depressive symptoms for a randomised trial were reviewed and assessed using the modified version of the Beers' Criteria. The association between inappropriate medication use and various population characteristics was assessed using Chi-square statistics and logistic regression analyses. RESULTS: The mean age was 81 (±4.3) years and 59% were women. The median number of medications used was 6 (range 1-21 medications). The most commonly prescribed potentially inappropriate medications were amitriptyline, dextropropoxyphene, quinine and benzodiazepines. Almost half (49%) of the participants were prescribed at least one potentially inappropriate medication; 29% were considered to suffer significant depressive symptoms (Geriatric Depression Scale ≥5) and no differences were found in the number of inappropriate medications used between those with and without significant depressive symptoms (Chi-square 0.005 p=0.54). DISCUSSION: Potentially inappropriate medication use, as per the modified Beers' Criteria, is very common among community-dwelling older people with depressive symptoms. However, the utility of the Beers' Criteria is lessened by lack of clinical correlation. Ongoing research to examine outcomes related to apparent inappropriate medication use is needed

Assessment of “Carbopeaking” in a hydropeaking-impacted river in the Italian Alpine area

Hydropeaking (i.e., rapid and frequent artificial flow fluctuations caused by reservoir-operated hydropower production) is a much-investigated river stressor, and has been associated, among others, to sudden changes in temperature (“thermopeaking”), underwater soundscape (“soundpeaking”), total dissolved gas saturation (“saturopeaking”). We have recently started investigating the “carbopeaking”, i.e., variations of greenhouse gas (mainly CO2) concentrations and evasion fluxes through the water-air interface associated with hydropeaks. Here we report on the methodology and preliminary results from a field-measurement campaign conducted in a single-thread Alpine river (River Noce, Italy) during multiple hydropeaking events. The analysis of water samples collected in the upstream reservoir showed CO2 oversaturation in the hypolimnion, around the depth of the hydropower intake system. In the Noce reach upstream of the hydropower plant outlet (i.e., in a residual flow stretch), the CO2 concentrations displayed diel fluctuations around the atmospheric equilibrium concentration, likely driven by diurnal primary production. Conversely, water released at the hydropower outlet during hydropeaking were consistently oversaturated in CO2 relative to the atmosphere, in agreement with the concentrations in the reservoir’s hypolimnetic water. As a result, hydropeaking events were associated with an alteration of the sub-daily patterns of CO2 concentration downstream of the hydropower outlet which, combined with higher gas exchange velocities occurring during higher flow rates, can cause periods of enhanced CO2 emissions. The results highlight the potential impact of hydropeaking on greenhouse gas emissions, demonstrating the need to account for sub-daily variations of flow and gas concentration to accurately quantify carbon balances in rivers impacted by hydropower

Coastal vulnerability assessment: through regional to local downscaling of wave characteristics along the Bay of Lalzit (Albania)

Coastal vulnerability is evaluated against inundation risk triggered by wave run-up through the evaluation of vulnerability levels (referred to as VLs) introduced by Bosom and Jiménez (2011). VLs are assessed through different wave climate characterizations, referring to regional (offshore wave climate) or local (nearshore wave climate) scales. The study is set along the Bay of Lalzit, a coastal area near Durrës (Albania). The analysis reveals that the results vary due to uncertainties inherent in the run-up estimation, showing that the computational procedure should be developed by taking into account detailed information about the local wave climate. Different approaches in choosing wave characteristics for run-up estimation significantly affect the estimate of shoreline vulnerability. The analysis also shows the feasibility and challenges of applying VL estimates in contexts characterized by limited data availability through targeted field measurements of the coast geomorphology and an overall understanding of the recent coastal dynamics and related controlling factors.</p

Wnt Signaling Upregulates Teneurin-3 Expression via Canonical and Non-canonical Wnt Pathway Crosstalk

Teneurins (Tens) are a highly conserved family of proteins necessary for cell-cell adhesion. Tens can be cleaved, and some of their proteolytic products, such as the teneurin c-terminal associated-peptide (TCAP) and the intracellular domain (ICD), have been demonstrated to be biologically active. Although Tens are considered critical for central nervous system development, they have also been demonstrated to play important roles in adult tissues, suggesting a potential link between their deregulation and various pathological processes, including neurodegeneration and cancer. However, knowledge regarding how Ten expression is modulated is almost absent. Relevantly, the functions of Tens resemble several of the effects of canonical and non-canonical Wnt pathway activation, including the effects of the Wnt pathways on neuronal development and function as well as their pivotal roles during carcinogenesis. Accordingly, in this initial study, we decided to evaluate whether Wnt signaling can modulate the expression of Tens. Remarkably, in the present work, we used a specific inhibitor of porcupine, the key enzyme for Wnt ligand secretion, to not only demonstrate the involvement of Wnt signaling in regulating Ten-3 expression for the first time but also reveal that Wnt3a, a canonical Wnt ligand, increases the expression of Ten-3 through a mechanism dependent on the secretion and activity of the non-canonical ligand Wnt5a. Although our work raises several new questions, our findings seem to demonstrate the upregulation of Ten-3 by Wnt signaling and also suggest that Ten-3 modulation is possible because of crosstalk between the canonical and non-canonical Wnt pathways