Vest, R. | Search bioRxiv

bioRxiv2023

Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons

Aging is the most prominent risk factor for Alzheimers disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-Tau and A{beta}, resembling those in AD patient and APP mouse brains. Quantitative tNeuron proteomics identify aging and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Supporting lysosomal deficits centrality in AD, compounds ameliorating lysosomal function reduce A{beta} deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of aging and AD.

cell biology↗

bioRxiv2021

A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk

The human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms--the blood-brain barrier--impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimers disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed in situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.

neuroscience↗