Increased expression of the proapoptotic presenilin associated protein is involved in neuronal tangle formation in human brain.

Presenilin-associated protein (PSAP) is a mitochondrial proapoptotic protein as established in cell biology studies. It remains unknown whether it involves in neurodegenerative diseases. Here, we explored PASP expression in adult and aged human brains and its alteration relative to Alzheimer-disease (AD)-type neuropathology. In pathology-free brains, light PASP immunoreactivity (IR) occurred among largely principal neurons in the cerebrum and subcortical structures. In the brains with AD pathology, enhanced PSAP IR occurred in neuronal and neuritic profiles with a tangle-like appearance, with PSAP and pTau protein levels elevated in neocortical lysates relative to control. Neuronal/neuritic profiles with enhanced PSAP IR partially colocalized with pTau, but invariably with Amylo-Glo labelled tangles. The neuronal somata with enhanced PASP IR also showed diminished IR for casein kinase 1 delta (Ck1δ), a marker of granulovacuolar degeneration; and diminished IR for sortilin, which is normally expressed in membrane and intracellular protein sorting/trafficking organelles. In old 3xTg-AD mice with ß-amyloid and pTau pathologies developed in the brain, PSAP IR in the cerebral sections exhibited no difference relative to wildtype mice. These findings indicate that PSAP upregulation is involved in the course of tangle formation especially in the human brain during aging and in AD pathogenesis.

Doublecortin-Expressing Neurons in Human Cerebral Cortex Layer II and Amygdala from Infancy to 100 Years Old.

A cohort of morphologically heterogenous doublecortin immunoreactive (DCX +) "immature neurons" has been identified in the cerebral cortex largely around layer II and the amygdala largely in the paralaminar nucleus (PLN) among various mammals. To gain a wide spatiotemporal view on these neurons in humans, we examined layer II and amygdalar DCX + neurons in the brains of infants to 100-year-old individuals. Layer II DCX + neurons occurred throughout the cerebrum in the infants/toddlers, mainly in the temporal lobe in the adolescents and adults, and only in the temporal cortex surrounding the amygdala in the elderly. Amygdalar DCX + neurons occurred in all age groups, localized primarily to the PLN, and reduced in number with age. The small-sized DCX + neurons were unipolar or bipolar, and formed migratory chains extending tangentially, obliquely, and inwardly in layers I-III in the cortex, and from the PLN to other nuclei in the amygdala. Morphologically mature-looking neurons had a relatively larger soma and weaker DCX reactivity. In contrast to the above, DCX + neurons in the hippocampal dentate gyrus were only detected in the infant cases in parallelly processed cerebral sections. The present study reveals a broader regional distribution of the cortical layer II DCX + neurons than previously documented in human cerebrum, especially during childhood and adolescence, while both layer II and amygdalar DCX + neurons persist in the temporal lobe lifelong. Layer II and amygdalar DCX + neurons may serve as an essential immature neuronal system to support functional network plasticity in human cerebrum in an age/region-dependent manner.

Health Risk Assessment of Inhalation Exposure to Airborne Particle-Bound Nitrated Polycyclic Aromatic Hydrocarbons in Urban and Suburban Areas of South China.

Airborne particulates (PM2.5 and TSP) were collected from outdoor and indoor areas at urban (Haizhu District) and suburban (Huadu District) sites from 2019 to 2020 in Guangzhou. Three nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) in the airborne particulates were identified by a gas chromatograph equipped with a triple-quadrupole mass spectrometer. In the Haizhu District and Huadu District, the nitro-PAH concentrations in PM2.5 and TSP did not show a significant decrease from winter to summer. From 2019 to 2020, the difference in the average concentration of nitro-PAHs in PM2.5 and TSP in Guangzhou was relatively low and had no statistical significance. The diagnostic ratios of 2-nitrofluorene (2-NF)/1-nitropyrene (1-NP) in TSP are less than five, while for 2-NF/1-NP in outdoor PM2.5 in the summer of 2019 and 2020 are more than five, which indicates that nitro-PAHs in the atmospheric PM2.5 in Guangzhou during summer mainly originated from the secondary formation of atmospheric photochemical reactions between parent PAHs and oxidants (·OH, NO3, and O3). 9-Nitroanthracene (9-NT) made the most significant contribution to the total nitro-PAH concentration. The incremental lifetime cancer risks (ILCRs) of nitro-PAHs in PM2.5 and TSP by inhalation exposure indicated low potential health risks in the urban-suburban of Guangzhou.

Intraneuronal sortilin aggregation relative to granulovacuolar degeneration, tau pathogenesis and sorfra plaque formation in human hippocampal formation.

Extracellular ß-amyloid (Aß) deposition and intraneuronal phosphorylated-tau (pTau) accumulation are the hallmark lesions of Alzheimer's disease (AD). Recently, "sorfra" plaques, named for the extracellular deposition of sortilin c-terminal fragments, are reported as a new AD-related proteopathy, which develop in the human cerebrum resembling the spatiotemporal trajectory of tauopathy. Here, we identified intraneuronal sortilin aggregation as a change related to the development of granulovacuolar degeneration (GVD), tauopathy, and sorfra plaques in the human hippocampal formation. Intraneuronal sortilin aggregation occurred as cytoplasmic inclusions among the pyramidal neurons, co-labeled by antibodies to the extracellular domain and intracellular C-terminal of sortilin. They existed infrequently in the brains of adults, while their density as quantified in the subiculum/CA1 areas increased in the brains from elderly lacking Aß/pTau, with pTau (i.e., primary age-related tauopathy, PART cases), and with Aß/pTau (probably/definitive AD, pAD/AD cases) pathologies. In PART and pAD/AD cases, the intraneuronal sortilin aggregates colocalized partially with various GVD markers including casein kinase 1 delta (Ck1δ) and charged multivesicular body protein 2B (CHMP2B). Single-cell densitometry established an inverse correlation between sortilin immunoreactivity and that of Ck1δ, CHMP2B, p62, and pTau among pyramidal neurons. In pAD/AD cases, the sortilin aggregates were reduced in density as moving from the subiculum to CA subregions, wherein sorfra plaques became fewer and absent. Taken together, we consider intraneuronal sortilin aggregation an aging/stress-related change implicating protein sorting deficit, which can activate protein clearance responses including via enhanced phosphorylation and hydrolysis, thereby promoting GVD, sorfra, and Tau pathogenesis, and ultimately, neuronal destruction and death.

Chiral gold clusters functionalized two-dimensional nanoparticle films to regulate the adhesion and differentiation of stem cells.

Chirality has been proved to play a significant role in tuning cell behaviors and controlling cellular functions. Up to now, almost all the chirality origins of extracellular microenvironment are belong to chiral ligands induction or direct chiral patterns. In this study, chiral gold nanoclusters (L/D-AuNC) loaded on two-dimensional gold nanoparticle films (L/D-film) with multiple chirality origins were prepared to regulate the adhesion and differentiation of mouse bone marrow mesenchymal stem cells (MSCs). MSCs on the D-film exhibited higher cell density and larger spreading area, and more cells differentiated into osteoblasts. Compared with D-film, L-film has a lower cell density and smaller spreading area, and more adipoblasts are achieved. The corresponding expression results of osteogenic differentiation marker (RUNX2) also confirmed the above experimental phenomenon. These results demonstrated that the chirality of clusters has great effect on the direction of cell fate.