The Neurovascular Unit Dysfunction in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.     

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.     

3‐D Printing and Development of Fluoropolymer Based Reactive Inks

Engineering reactive materials is an ever present goal in the energetics community. The desire is to have energetics configured in such a manner that performance is tailored and energy delivery can be targeted. Additive manufacturing (3‐D printing) is one area that could significantly improve our capabilities in this area, if adequate formulations are developed. In this paper, fluoropolymer based reactive inks are developed with micron (mAl) and nanoscale aluminum (nAl) serving, as the fuel at high solids loading (up to 67 wt%) and their viscosity required for 3‐D printing is detailed. For the pen‐type technique and valves used in this work, it is required to have viscosities on the order of 10⁴–10⁵ cP. For printed traces with apparent diameters under <500 μm, the combustion velocities for both micron and nano scale aluminum formulations, are approximately identical: 30 ± 3 versus 32 ± 2 mm s^?1, respectively. Further increasing the apparent diameter is shown to increase the combustion velocity in the case of the nanoscale aluminum formulation by four‐fold over that of the micron scale aluminum formulation, but it plateaus as it approaches an apparent diameter of 2 mm. The results suggest with proper architecture that tailorable combustion rates and energy delivery are feasible.

     

Effect of brine thawing/salting on endogenous enzyme activity and sensory quality of Iberian dry-cured ham

Simultaneous brine thawing/salting process was applied as an alternative to traditional pile salting process using 51 frozen Iberian hams. The effect of this type of salting process on endogenous enzyme activity and sensory quality of Iberian dry-cured hams was analysed. The frozen hams were simultaneously thawed and salted with saturated brine, with and without vacuum pulses, and were compared to hams thawed under refrigeration and traditionally salted. The peptidase and lipase activities were measured at the end of salting and post-salting stages. The activity of cathepsin B+L was reduced in the two brine salted batches while few differences among batches were observed for the other peptidases. Several lipase activities were significantly reduced in the two brine salted batches. The brine thawed processing affected the free fatty acid content at the different stages although the differences were more appreciated at the beginning of the process and no differences were observed at the end. The long ripening time makes these differences negligible and the consumer did not appreciate any differences between the sensory quality of Iberian brine/thawed hams and traditional Iberian thawed pile salted hams.     

Dipeptidyl peptidase activities along the processing of Serrano dry-cured ham

The activity of pork muscle dipeptidyl peptidases I, II, III, and IV was followed during the processing of Serrano dry-cured ham. The effects of NaCl, pH, and temperature on these enzymes have also been studied for a better understanding of their importance in ham processing. The lysosomal enzymes DPP I and DPP II showed maximal activity at pH around 5.5-6.0, i.e., close to the pH in ham. At low temperatures, only DPP I and DPP IV showed relevant activity. NaCl considerably inhibited DPP activities except DPP I which was only slightly affected. Dipeptidyl peptidases remained active during the whole process except DPP II whose activity disappeared after 240 days of dry-curing.     

Activity of cathepsin D as affected by chemical and physical dry-curing parameters

The effect of curing agents (nitrate, glucose, ascorbic acid and chloride) and physical parameters (temperature, water activity and pressure) on porcine muscle cathepsin D has been studied. Chloride (in the assayed range 0 to 75 g Cl-/L) showed a strong inhibitory effect. Nitrate (in the assayed range 0 to 800 mg/L) and high concentrations of ascorbic acid (4 to 8 g/L) slightly inhibited cathepsin D. However, its activity increased when glucose was added up to 4 g/L. Cathepsin D activity was maximal when incubated at 33 to 53 degrees C, was affected by a decrease in water activity and unaffected by pressure.     

Effect of Debaryomyces spp. on the proteolysis of dry-fermented sausages

The effect of the addition of Debaryomyces spp. on the microbial, chemical properties and degradation of meat proteins in dry fermented sausages was investigated. The manufacture of dry fermented sausages with Debaryomyces spp. produced a slow decline in pH during early drying stage. However, the final product had lower ammonia, and higher acetic and d-lactic acids without producing any effect on the final pH. Sarcoplasmic proteins were not affected by Debaryomyces spp. but the degradation of myofibrillar proteins was accelerated at the beginning of the drying stage even though the final sausage, inoculated with Debaryomyces spp., had lower myofibrillar proteolysis. The content of free amino acids was similar at the beginning of the drying stage for all the studied batches. However, the high differences in the content of free amino acids at the end of the process could be attributed to the Debaryomyces spp. activity. The addition of a higher amount of Debaryomyces spp. did not contribute to a major proteolysis degree.