We report for the first time that small molecule-based radiodiodinated ligands, showing selective binding to Aβ aggregates, cross the intact blood−brain barrier by simple diffusion. Four novel ligands showing preferential labeling of amyloid aggregates of Aβ(1−40) and Aβ(1−42) peptides, commonly associated with plaques in the brain of people with Alzheimer's disease (AD), were developed. Two 125I-labeled styrylbenzenes, (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene, 12 (ISB), and (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene, 13 (IMSB), and two 125I-labeled thioflavins, 2-[4‘-(dimethylamino)phenyl]-6-iodobenzothiazole, 18a (TZDM), and 2-[4‘-(4‘ ‘-methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, 18b (TZPI), were prepared at a high specific activity (2200 Ci/mmol). In vitro binding studies of these ligands showed excellent binding affinities with K d values of 0.08, 0.13, 0.06, and 0.13 nM for aggregates of Aβ(1−40) and 0.15, 0.73, 0.14, and 0.15 nM for aggregates of Aβ(1−42), respectively. Interestingly, under a competitive-binding assaying condition, different binding sites on Aβ(1−40) and Aβ(1−42) aggregates, which are mutually exclusive, were observed for styrylbenzenes and thioflavins. Autoradiography studies of postmortem brain sections of a patient with Down's syndrome known to contain primarily Aβ(1−42) aggregates in the brain showed that both [125I]18a and [125I]18b labeled these brain sections, but [125I]13, selective for Aβ(1−40) aggregates, exhibited very low labeling of the comparable brain section. Biodistribution studies in normal mice after an iv injection showed that [125I]18a and [125I]18b exhibited excellent brain uptake and retention, the levels of which were much higher than those of [125I]12 and [125I]13. These findings strongly suggest that the new radioiodinated ligands, [125I]12 (ISB), [125I]13 (IMSB), [125I]18a (TZDM), and [125I]18b (TZPI), may be useful as biomarkers for studying Aβ(1−40) as well as Aβ(1−42) aggregates of amyloidogenesis in AD patients.

No abstract

No abstract

Although alpha-synuclein (alpha-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of alpha-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight alpha-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that alpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in alpha-syn.

Why did COVID-19 hit some countries harder than others? While this question is usually answered based on demographics (e. g., population age), health policy (e.g., quarantine), or economic factors, we argue that cultural variance across countries is just as crucial in understanding how susceptible a society is to the COVID-19 outbreak. To test this hypothesis, we first analyzed data collected across 69 countries and examined the relationship between culture and the impact of COVID. Next, we conducted two studies to validate our findings further and explore the mechanism at hand. As expected, we found that the more individualistic (vs. collectivistic) a country was, the more COVID-19 cases and mortalities it had. We also found that the more individualistic participants were, the higher the chances they would not adhere to epidemic prevention measures. These findings are important in understanding the spread of the pandemic, devising optimal exit strategies from lockdowns, and persuading the population to get the new vaccine against the virus.