Search

Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.

Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1–3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1–3. 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 disease4–6. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans7and linked to cognitive function8—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.

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1—these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2—or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function. Single-cell transcriptomic analysis of neurogenic niches in young and old mice reveals that T cells infiltrate the neurogenic niches of old mice and inhibit the proliferation of neural stem cells, in part through expression of interferon-γ.

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

An analysis of mice carrying the protein tau — a hallmark of Alzheimer’s disease — reveals that immune cells collaborate to drive tau-mediated neurodegeneration, and that drugs already in use in the clinic can combat this decline.

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.

The 25-cm uplift in Southern California is interpreted as being due to dilatancy of the crust, which started in 1961 along the San Andreas fault and spread laterally during 1964–69. The San Fernando earthquake of 1971 occurred in part of the dilatant volume, and is interpreted as a sideshow of a future repetition of the 1857 San Andreas break, which had a magnitude > 8.

Large earthquakes often occur as multiple ruptures reflecting strong variations of stress level along faults. Dense instrument networks with which the volcano Kilauea is monitored provided detailed data on changes of seismic velocity, strain accumulation and earthquake occurrence rate before the 1975 Hawaii 7.2-mag earthquake. During the ∼4 yr of preparation time the mainshock source volume had separated into crustal volumes of high stress levels embedded in a larger low-stress volume, showing respectively high- and low-stress precursory anomalies.

In May 1985 we predicted1that an earthquake would occur on the San Andreas fault near Stone Canyon, California within a year. The prediction was based on the observation of seismic quiescence–defined as a significant decrease in the average occurrence rate of earthquakes within the source volume of the future mainshock. A mainshock of magnitude ML= 4.6 occurred on 31 May 1986, rupturing exactly the specified segment of the fault. This is the first successful prediction of an earthquake along the San Andreas fault, and the probability to have come true by chance is <5%. Although the prediction addressed only a small main-shock, its success was significant because the location, size and occurrence time were correctly specified for an earthquake in a populated area. Larger earthquakes will undoubtedly be successfully predicted by the same method in the future, but the major segments of the San Andreas fault near San Francisco and Los Angeles have such a low-background seismicity rate that the method will probably not be applicable there.

Actin heterogeneity is well known: within one vertebrate species up to six forms of actin, differing in isoelectric point, amino acid composition and antigenic sites have been described and their synthesis shown to be tissue specific1–8. In Drosophila melanogaster actin genes have been located at six distinct sites on the chromosomes9,10and three forms of actin (synthesized and/or accumulated in different amounts in different tissues11–14) have been distinguished electrophoretically. In view of the obvious importance of actin in muscle, it was of interest to search in Drosophila for abnormalities of actin in flightless mutants which primarily affect fibrillar flight muscles, such as raised (rsd)14–20. Here we report that the actin pattern in two types of adult skeletal muscles is differently affected by the rsd mutation. Since rsd is located on the right arm of the third chromosome25, which is not the known position of the structural genes of actin9,10, we conclude that rsd is a regulatory gene.

South of Crete, the seismicity rate was constant in space and time between 1950 and 1978, but in the Western Hellenic Trench the rate was the same as that south of Crete until 1962, whereupon it decreased by 80%. We now suggest that the anomaly constitutes a warning of large earthquakes within the coming decade.

P-VELOCITY decreases before earthquakes1–4can be observed by monitoring the average P-residual at seismic stations near the focus5–7. The P-residual is the difference between the observed travel time from an epicentre to a station and that computed theoretically on the basis of some Earth model and a least squares estimate of the earthquake location and origin time. If the P-velocity in the crust underneath a seismic station is decreased temporarily, each seismic wave will arrive somewhat later during the premonitory period. Before three thrust5,6,18and one strike-slip event7the delay was found to be approximately 0.4 s.

The mutual affinities of pinnipeds (the 'fin-footed' members of the placental mammal order Carnivore) have been the subject of controversy for more than a century1,2. Disagreement centres over whether the origin of the group from a terrestrial ancestry involved a single or multiple marine invasion(s). Particularly since influential papers of the late 1950s and '60s (refs 3, 4), the dual origin of pinnipeds—sea lions (otariids) plus walruses (odobenids) from bear-like forms, and 'true' seals (phocids) from weasel- or otter-like forms—has become the overwhelmingly dominant view in the morphological systematic literature5–8, a point reflected by its acceptance in several general texts9–11. Anatomical evidence from a survey of appendicular osteology presented here contradicts this notion and suggests radical alteration of currently accepted hypotheses of the relationship of the major pinniped lineages. This evidence strongly suggests a single (monophyletic) origin for the group, a finding in agreement with certain biomolecular results12–15.

TELESEISMIC residuals of the Matsushiro seismic station clearly indicate a decrease in P-wave velocity underneath this station beginning three years before the Matsushiro earthquake swarm of 1965. This is the first instance where premonitory velocity changes have been observed before strike slip faulting1,2. It is concluded that P-wave residuals provide another means for assessment of the earthquake risk near seismic stations.

SEISMIC ray tracing1–4has shown that the slabs of lithosphere which descend into the mantle in subduction zones are approximately 80 km thick. Within these slabs there are thin zones in which earthquakes occur5. Here I estimate the thickness of the seismic zone in Tonga as ∼11 km, from the source dimensions of the large intermediate earthquakes.

DURING the course of our recent investigations of the microbiota of air and soil in Antarctica, a food cache which was partially covered by a snow embankment was found at Cape Evans, Ross Island. The cache was left at this base camp by Captain Robert Falcon Scott of the British Royal Navy prior to his ill-fated expedition to the South Pole in 1911, and consisted of various types of tinned foods together with a glass container of granular, dehydrated bakers' yeast (1 lb. capacity).