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"Yang, Andrew"
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The ping-pong queen of Chinatown
Starting a film club at school, Felix Ma asks Cassie Chow, a bubbly high school senior who shares his anxieties about the future and parental expectations, to star in his short film, but his lighthearted mockumentary unexpectedly uncovers their most painful memories.
Book
Dysregulation of brain and choroid plexus cell types in severe COVID-19
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms
1
–
3
. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease
4
–
6
. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans
7
and linked to cognitive function
8
—is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.
Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.
Journal Article
Exercise plasma boosts memory and dampens brain inflammation via clusterin
Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration
1
. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus
2
–
4
, yet little is known about the factors and mechanisms that mediate these effects. Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer’s disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.
Plasma from voluntarily running mice reduces baseline expression of neuroinflammatory genes and experimentally induced brain inflammation when infused into sedentary mice.
Journal Article
A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
The human brain vasculature is of great medical importance: its dysfunction causes disability and death
1
, and the specialized structure it forms—the blood–brain barrier—impedes the treatment of nearly all brain disorders
2
,
3
. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer’s disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer’s disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer’s disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer’s disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.
A method called vessel isolation and nuclei extraction for sequencing (VINE-seq) produces a molecular map of vascular and perivascular cell types in the human brain and reveals their contributions to Alzheimer’s disease risk.
Journal Article
Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1
An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular–immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of
Vcam1
in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood–brain barrier as a possible target to treat age-related neurodegeneration.
The detrimental effects of aged blood on cognition and nervous system function in mice can be combatted by targeting brain endothelial cell dysfunction via inhibition of aberrant VCAM1 signaling at the blood–brain barrier.
Journal Article
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
Alzheimer’s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function
1
. However, little is known about the contribution of the adaptive immune response in Alzheimer’s disease
2
. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer’s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer’s disease that consists of increased numbers of CD8
+
T effector memory CD45RA
+
(T
EMRA
) cells. In a second cohort, we found that CD8
+
T
EMRA
cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8
+
T
EMRA
cells in the cerebrospinal fluid of patients with Alzheimer’s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer’s disease to two separate Epstein–Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer’s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.
An integrated analysis of several cohorts shows that clonal, antigen-experienced T cells are found in the cerebrospinal fluid of patients with Alzheimer’s disease, suggesting that the adaptive immune system has a role in age-related neurodegeneration.
Journal Article
Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17
Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing
1
–
3
. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds
4
,
5
. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.
Fgf17 in young CSF boosts oligodendrocyte progenitor cell proliferation and differentiation in the aged hippocampus, improving memory function.
Journal Article
An exercise-inducible metabolite that suppresses feeding and obesity
Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases
1
–
5
. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear
6
. Here we show that exercise stimulates the production of
N
-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2
+
cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
A newly identified exercise-induced signalling metabolite—an amidated conjugate of lactate and phenylalanine—can reduce food intake and improve blood glucose homeostasis.
Journal Article
Physiological blood–brain transport is impaired with age by a shift in transcytosis
The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability
1
–
3
. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins
4
,
5
. Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.
Tagging and tracking the blood plasma proteome as a discovery tool reveals widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which the brain endothelium regulates this process with age.
Journal Article
Growth of Lumbosacral Perineural (Tarlov) Cysts: A Natural History Analysis
Abstract
BACKGROUND
Tarlov cysts (TC) are commonly found spinal perineural cysts. Symptomatic TCs are rare, however, and there is no consensus on their pathogenesis and optimal management.
OBJECTIVE
To characterize cyst growth in patients with symptomatic TCs.
METHODS
This is a retrospective cohort study of 28 subjects, evaluated for symptomatic TCs (2011-2017). Each of the subjects had multiple magnetic resonance imaging (MRIs) across time and was included in a natural history analysis.
RESULTS
A total of 42 TCs were identified across the 28 subjects, of which 7 cysts (17%) across 5 subjects demonstrated growth. Across a mean follow-up of 4.7 ± 1.8 years, TCs grew at a relative rate of 2.9 ± 2.6% in the anteroposterior, 4.3 ± 3.8% in the craniocaudal, and 1.4 ± 1.4% in the transverse dimensions per year. None of the cysts decreased in size between successive MRIs. Symptoms of cerebrospinal fluid (CSF) hypotension (positional headaches) were positive predictors of prior cyst growth on logistic regression (P = 0.02, odds ratio = 10). A total of 2 of the 5 subjects were initially asymptomatic from their TCs, and developed symptoms during the period of cyst growth, whereas 2 others experienced worsening of their symptoms during cyst growth.
CONCLUSION
We report on the growth of TCs, which is consistent with a widely-held theory that hydrostatic and pulsatile forces of CSF along with a ball-valve phenomenon allow for continuous dilation of TCs.
Journal Article