Recent human trials of treatments for Alzheimer’s disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-βAβ? plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Aβ were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Aβ. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression.
The intraluminal filament model of middle cerebral artery occlusion (MCAO) in mice and rats has been plagued by inconsistency, owing in part to the multitude of variables requiring control. In this study we investigated the impact of several major variables on survival rate, lesion volume, neurological scores, cerebral blood flow (CBF) and body weight including filament width, time after reperfusion, occlusion time and the choice of surgical method. Using the Koizumi method, we found ischemic injury can be detected as early as 30 min after reperfusion, to a degree that is not statistically different from 24 h post-perfusion, using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. We also found a distinct increase in total lesion volume with increasing occlusion time, with 30–45 min a critical time for the development of large, reproducible lesions. Furthermore, although we found no significant difference in total lesion volume generated by the Koizumi and Longa methods of MCAO, nor were survival rates appreciably different between the two at 4 h after reperfusion, the Longa method produces significantly greater reperfusion. Finally, we found no statistical evidence to support the exclusion of data from animals experiencing a CBF reduction of <70% in the MCA territory following MCAO, using laser-Doppler flowmetry. Instead we suggest the main usefulness of laser-Doppler flowmetry is for guiding filament placement and the identification of subarachnoid haemorrhages and premature reperfusion. In summary, this study provides detailed evaluation of the Koizumi method of intraluminal filament MCAO in mice and a direct comparison to the Longa method.
Multifunctional nanoparticles are increasingly employed to improve biological efficiency in medical imaging, diagnostics, and treatment applications. However, even the most well-established nanoparticle platforms rely on multiple-step wet-chemistry approaches for functionalization often with linkers, substantially increasing complexity and cost, while limiting efficacy. Plasma dust nanoparticles are ubiquitous in space, commonly observed in reactive plasmas, and long regarded as detrimental to many manufacturing processes. As the bulk of research to date has sought to eliminate plasma nanoparticles, their potential in theranostics has been overlooked. Here we show that carbon-activated plasma-polymerized nanoparticles (nanoP 3 ) can be synthesized in dusty plasmas with tailored properties, in a process that is compatible with scale up to high throughput, low-cost commercial production. We demonstrate that nanoP 3 have a long active shelf life, containing a reservoir of long-lived radicals embedded during their synthesis that facilitate attachment of molecules upon contact with the nanoparticle surface. Following synthesis, nanoP 3 are transferred to the bench, where simple one-step incubation in aqueous solution, without the need for intermediate chemical linkers or purification steps, immobilizes multiple cargo that retain biological activity. Bare nanoP 3 readily enter multiple cell types and do not inhibit cell proliferation. Following functionalization with multiple fluorescently labeled cargo, nanoP 3 retain their ability to cross the cell membrane. This paper shows the unanticipated potential of carbonaceous plasma dust for theranostics, facilitating simultaneous imaging and cargo delivery on an easily customizable, functionalizable, cost-effective, and scalable nanoparticle platform.
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