Biology subjects

saiyin, H.

Publications and source records attributed to saiyin, H..

3 recordsLinked to original sources

bioRxiv2025

Peptides alleviate cognitive impairment by inhibiting and disassembling amyloid-beta aggregates in Alzheimer disease

Alzheimers disease (AD) is a devasting neurodegenerative disorder characterized by {beta}-amyloid formation, further exacerbated by RIPK1/RIPK3 necrosome-induced programmed necrosis (necroptosis). We previously showed that the RIPK1/RIPK3 necrosome forms a functional amyloid complex using its RIP homotypic interaction motifs (RHIMs). Here, we discovered that the core RIPK1/RIPK3 necrosome shares strikingly structural similarity to the C-terminal region of {beta}-amyloid (A{beta}42), and the RHIM-derived tetrapeptides (IQIG or VQVG) directly inhibit A{beta} aggregation, disassemble preformed A{beta} fibrils (PFFs), and reduce RIPK1 polymerization. Also, the peptides exhibit effective membrane permeability and could reduce A{beta}40 or A{beta}42-induced neural death and TNF-induced necroptosis in SH-SY5Y cells. IQIG and VQVG injected by ICV increase learning and memory abilities by reducing A{beta} plaques and hyperphosphorylated tau in the cortex and hippocampus of APP/PS1 double-transgenic mice. Mechanistically, the peptides directly interact with A{beta} to block A{beta} aggregation and alleviate microglia-mediated neuroinflammation. Strikingly, single-cell RNA sequencing revealed that the peptides-treated AD transgenic mice restored neuronal homeostasis with increased GABAergic neurons and decreased glutamatergic neurons. Furthermore, total cell-cell interaction strength increased while the AD risk gene Apoe expression decreased in the specific oligodendrocyte subtype of peptides-treated AD mice. Thus, our findings revealed that the peptides could improve cognition and memory capabilities and serve as promising structural templates for potential drugs against AD.

neuroscience↗

bioRxiv2024

Endogenous Huntingtin aggregates are a huge organized scaffold and mold for Golgi apparatus impaired by mutant Huntingtin protein

Abstract Huntingtin (HTT) is a naturally aggregating protein that causes Huntington's disease (HD) when its polyglutamine (polyQ) tract exceeds 38 repeats. Despite its importance, the biology of HTT aggregates remains poorly defined. Here, using high resolution imaging of cells derived from HD families, we redefine polyQ assemblies, traditionally regarded as pathogenic aggregates, as dynamic and structurally organized intracellular compartments resembling knitted-fabric patches. These assemblies closely associate with and encircle the Golgi apparatus, integrating Golgi ribbons and stacks to form a previously unrecognized polyQ assembly-Golgi complex. Mechanistically, fragmentation of polyQ assemblies is dynamically coupled with mitotic Golgi fragmentation, whereas inhibition of ADP-ribosylation factor (ARF) function by Brefeldin A disrupts and fragments the complex, revealing an intimate structural and functional coupling between polyQ assemblies and Golgi architecture. The presence of mutant HTT (mHTT) destabilizes these assemblies and complexes, altering their response to nutrient deprivation and autophagy enhancers but not to antisense oligonucleotide (ASO) therapy. Functionally, polyQ assemblies in HD cells compromise the scaffolding capacity of the Golgi apparatus, clathrin-coated vesicles, and ARF1, impair Golgi glycosylation, and promote aberrant neuronal firing activity. Collectively, these findings establish polyQ assemblies as dynamic structural regulators of Golgi organization and function and demonstrate that mHTT disrupts the homeostatic dynamics of the polyQ assembly-Golgi complex, leading to Golgipathy.

pathology↗

bioRxiv2024

Secondary microglia formation center in the human fetal brain

Yolk sac-derived microglia migrate and populate the brain during development, constituting 10-15% of the total brain cells. The human brain is the largest and most complex brain with the highest cognitive capacity among all species. Therefore, the limitations of rodent brain studies in interpreting the human brain are evident. By co-immunostaining microglia in 50 {micro}m fetal brain sections from 7.5 to 16 gestational weeks (gw) and combining high-resolution scanning, we identified a highly proliferative microglia aggregate (0.108-2.129 mm2) that expanded in Downs Syndrome fetal brain (4.168 mm2) and was located near the ganglion eminence, in which Ki67+ microglia accounted for 23.4% of total microglia compared to 6.3% in other brain regions. The microglia in the aggregates lack phagocytic bulbs, membrane ruffles, and long/branching processes compared to microglia in other brain regions. Introducing human microglia into cortical organoids, but not macrophages, replicated proliferative microglial aggregates on the brain organoid surface and sufficiently penetrated deeper regions of the cortical organoids. Penetrating microglia display phagocytic capacity, enhance immunity, and accelerate the maturation of brain organoids. The large proliferative microglial aggregate may be a unique secondary microglial formation center in the human fetal brain to compensate for the enormous microglial demands during brain expansion.

neuroscience↗