Our staff editors continue to share brilliant, thoughtful, and meaningful topics and articles in the recommended series.
This week, we would like to share the latest articles about Alzheimer disease.
Title: Focal-type, but not Diffuse-type, Amyloid Beta Plaques are Correlated with Alzheimer's Neuropathology, Cognitive Dysfunction, and Neuroinflammation in the Human Hippocampus
Authors: Fan Liu, Jianru Sun, Xue Wang, Sixuan Jin, Fengrun Sun, Tao Wang, Bo Yuan, Wenying Qiu, Chao Ma
Type: Original Article
Amyloid beta (Aβ) plaques are one of the hallmarks of Alzheimer’s disease (AD). However, currently available anti-amyloid therapies fail to show effectiveness in the treatment of AD in humans. It has been found that there are different types of Aβ plaque (diffuse and focal types) in the postmortem human brain. In this study, we aimed to investigate the correlations among different types of Aβ plaque and AD-related neuropathological and cognitive changes based on a postmortem human brain bank in China. The results indicated that focal plaques, but not diffuse plaques, significantly increased with age in the human hippocampus. We also found that the number of focal plaques was positively correlated with the severity of AD-related neuropathological changes (measured by the “ABC” scoring system) and cognitive decline (measured by the Everyday Cognitive Insider Questionnaire). Furthermore, most of the focal plaques were co-localized with neuritic plaques (identified by Bielschowsky silver staining) and accompanied by microglial and other inflammatory cells. Our findings suggest the potential of using focal-type but not general Aβ plaques as biomarkers for the neuropathological evaluation of AD.
Access this article: https://doi.org/10.1007/s12264-022-00927-5
Title: The therapeutic prospects and challenges of human neural stem cells for the treatment of Alzheimer's Disease
Authors: Chunmei Yue, Su Feng, Yingying Chen, Naihe Jing
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder associated with aging. Due to its insidious onset, protracted progression, and unclear pathogenesis, it is considered one of the most obscure and intractable brain disorders, and currently, there are no effective therapies for it. Convincing evidence indicates that the irreversible decline of cognitive abilities in patients coincides with the deterioration and degeneration of neurons and synapses in the AD brain. Human neural stem cells (NSCs) hold the potential to functionally replace lost neurons, reinforce impaired synaptic networks, and repair the damaged AD brain. They have therefore received extensive attention as a possible source of donor cells for cellular replacement therapies for AD. Here, we review the progress in NSC-based transplantation studies in animal models of AD and assess the therapeutic advantages and challenges of human NSCs as donor cells. We then formulate a promising transplantation approach for the treatment of human AD, which would help to explore the disease-modifying cellular therapeutic strategy for the treatment of human AD.
Access this article: http://dx.doi.org/10.20517/and.2022.12
Title: A "multi-omics" analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice
Authors: Giuseppe Barisano, Kassandra Kisler, Brent Wilkinson, Angeliki Maria Nikolakopoulou, Abhay P Sagare, Yaoming Wang, William Gilliam, Mikko T Huuskonen, Shu-Ting Hung, Justin K Ichida, Fan Gao, Marcelo P Coba, Berislav V Zlokovic
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2–3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2–5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.
Access this article: https://doi.org/10.1084/jem.20221137
Title: Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau
Authors: Jamshid Asadzadeh, Evelyne Ruchti, Wei Jiao, Greta Limoni, Catherine MacLachlan, Scott A. Small, Graham Knott, Ismael Santa-Maria, Brian D. McCabe
Alteration of the levels, localization or post-translational processing of the microtubule associated protein Tau is associated with many neurodegenerative disorders. Here we develop adult-onset models for human Tau (hTau) toxicity in Drosophila that enable age-dependent quantitative measurement of central nervous system synapse loss and axonal degeneration, in addition to effects upon lifespan, to facilitate evaluation of factors that may contribute to Tau-dependent neurodegeneration. Using these models, we interrogate the interaction of hTau with the retromer complex, an evolutionarily conserved cargo-sorting protein assembly, whose reduced activity has been associated with both Parkinson's and late onset Alzheimer’s disease. We reveal that reduction of retromer activity induces a potent enhancement of hTau toxicity upon synapse loss, axon retraction and lifespan through a specific increase in the production of a C-terminal truncated isoform of hTau. Our data establish a molecular and subcellular mechanism necessary and sufficient for the depletion of retromer activity to exacerbate Tau-dependent neurodegeneration.
Access this article: https://doi.org/10.1038/s41467-022-32683-5
Title: Aqp4 stop codon readthrough facilitates amyloid-β clearance from the brain
Authors: Darshan Sapkota, Colin Florian, Brookelyn M Doherty, Kelli M White, Kate M Reardon, Xia Ge, Joel R Garbow, Carla M Yuede, John R Cirrito, Joseph D Dougherty
Alzheimer’s disease is initiated by the toxic aggregation of amyloid-β. Immunotherapeutics aimed at reducing amyloid beta are in clinical trials but with very limited success to date. Identification of orthogonal approaches for clearing amyloid beta may complement these approaches for treating Alzheimer’s disease. In the brain, the astrocytic water channel Aquaporin 4 is involved in clearance of amyloid beta, and the fraction of Aquaporin 4 found perivascularly is decreased in Alzheimer’s disease. Further, an unusual stop codon readthrough event generates a conserved C-terminally elongated variant of Aquaporin 4 (AQP4X), which is exclusively perivascular. However, it is unclear whether the AQP4X variant specifically mediates amyloid beta clearance.
Here, using Aquaporin 4 readthrough-specific knockout mice that still express normal Aquaporin 4, we determine that this isoform indeed mediates amyloid beta clearance. Further, with high-throughput screening and counterscreening, we identify small molecule compounds that enhance readthrough of the Aquaporin 4 sequence and validate a subset on endogenous astrocyte Aquaporin 4. Finally, we demonstrate these compounds enhance brain amyloid-β clearance in vivo, which depends on AQP4X.
This suggests derivatives of these compounds may provide a viable pharmaceutical approach to enhance clearance of amyloid beta and potentially other aggregating proteins in neurodegenerative disease.
Access this article: https://doi.org/10.1093/brain/awac199