ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Magnetic skyrmions are swirling magnetic textures with novel characteristics suitable for future spintronic and topological applications. Recent studies confirmed the room-temperature stabilization of skyrmions in ultrathin ferromagnets. However, such ferromagnetic skyrmions show an undesirable topological effect, the skyrmion Hall effect, which leads to their current-driven motion towards device edges, where skyrmions could easily be annihilated by topographic defects. Recent theoretical studies have predicted enhanced current-driven behavior for antiferromagnetically exchange-coupled skyrmions. Here we present the stabilization of these skyrmions and their current-driven dynamics in ferrimagnetic GdFeCo films. By utilizing element-specific X-ray imaging, we find that the skyrmions in the Gd and FeCo sublayers are antiferromagnetically exchange-coupled. We further confirm that ferrimagnetic skyrmions can move at a velocity of ~50 m s−1 with reduced skyrmion Hall angle, |θSkHE| ~ 20°. Our findings open the door to ferrimagnetic and antiferromagnetic skyrmionics while providing key experimental evidences of recent theoretical studies.

Developing effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood–brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.

Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLP APT ) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patientderived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway.We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLP APT mice.