Tony Wyss-Coray, Postdoctoral Faculty Sponsor
Atlas of the aging mouse brain reveals white matter as vulnerable foci.
Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.
View details for DOI 10.1016/j.cell.2023.07.027
View details for PubMedID 37591239
A nanotherapeutic approach to selectively eliminate metastatic breast cancer cells by targeting cell surface GRP78.
Here, rational engineering of doxorubicin prodrug loaded peptide-targeted liposomal nanoparticles to selectively target metastatic breast cancer cells in vivo is described. Glucose-regulated protein 78 (GRP78), a heat shock protein typically localized in the endoplasmic reticulum in healthy cells, has been identified to home to the cell surface in certain cancers, and thus has emerged as a promising therapeutic target. Recent reports indicated GRP78 to be expressed on the cell surface of an aggressive subpopulation of stem-like breast cancer cells that exhibit metastatic potential. In this study, a targeted nanoparticle formulation with a GRP78-binding peptide (Kd of 7.4 ± 1.0 μM) was optimized to selectively target this subpopulation. In vitro studies with breast cancer cell lines showed the targeted nanoparticle formulation (TNPGRP78pep) achieved enhanced cellular uptake, while maintaining selectivity over the control groups. In vivo, TNPGRP78pep loaded with doxorubicin prodrug was evaluated using a lung metastatic mouse model and demonstrated inhibition of breast cancer cell seeding to lungs down at the level of negative control groups. Combined, this study established that specific-targeting of surface GRP78 expressing a subpopulation of aggressive breast cancer cells was able to inhibit breast cancer metastasis to lungs, and underpinned the significance of GRP78 in breast cancer metastasis.
View details for DOI 10.1039/d3nr00800b
View details for PubMedID 37526009
APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia.
bioRxiv : the preprint server for biology
Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.
View details for DOI 10.1101/2023.07.21.549930
View details for PubMedID 37546938
View details for PubMedCentralID PMC10401952
Activated immune cells drive neurodegeneration
2023; 615 (7953): 588-589
View details for Web of Science ID 000961443400002
- Activated immune cells drive neurodegeneration in an Alzheimer's model. Nature 2023; 615 (7953): 588-589
Isolation of mouse brain-infiltrating leukocytes for single cell profiling of epitopes and transcriptomes.
2021; 2 (2): 100537
High dimensional compositional and transcriptional profiling of heterogeneous brain-infiltrating leukocytes can lead to novel biological and therapeutic discoveries. High-quality single-cell leukocyte preparations are a prerequisite for optimal single cell profiling. Here, we describe a protocol for epitope and RNA-preserving dissociation of adult mouse brains and subsequent leukocyte purification and staining, which is adaptable to homeostatic and pathogenic brains. Leukocyte preparation following this protocol permits exquisite single-cell surface protein and RNA profiling in applications including CyTOF and CITE-seq. For complete details on the use and execution of this protocol, please refer to Guldner etal. (2020) and Golomb etal. (2020).
View details for DOI 10.1016/j.xpro.2021.100537
View details for PubMedID 34036283