Of mice and men's microglia: Microglia are immune system cells that function in protecting and maintaining the brain. Gosselin et al. examined the epigenetics and RNA transcripts from single microglial cells and observed consistent profiles among samples despite differences in age, sex, and diagnosis. Mouse and human microglia demonstrated similar microglia-specific gene expression profiles, as well as a shared environmental response among microglia collected either immediately after surgery (ex vivo) or after culturing (in vitro). Interestingly, those genes exhibiting differences in expression between humans and mice or after culturing were often implicated in neurodegenerative diseases. Science , this issue p. eaal3222

Linking enhancers to disease: Enhancers are genomic regions that regulate gene expression, sometimes in a cell-dependent manner. However, most of our knowledge of human brain cell–type enhancers derives from studies of bulk human brain tissue. Nott et al. examined chromatin and promoter activity in cell nuclei isolated from human brains. Genetic variants associated with brain traits and disease showed cell-specific patterns of enhancer enrichment. These data indicate that Alzheimer's disease is regulated by genetic variants within microglial cells, whereas psychiatric diseases tend to affect neurons. Science , this issue p. 1134

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 theAPOE4/4genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ inducesACSL1expression, 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.

Distinct gait characteristics like short steps and shuffling gait are prototypical signs commonly observed in Parkinson’s disease. Routinely assessed by observation through clinicians, gait is rated as part of categorical clinical scores. There is an increasing need to provide quantitative measurements of gait, e.g. to provide detailed information about disease progression. Recently, we developed a wearable sensor-based gait analysis system as diagnostic tool that objectively assesses gait parameter in Parkinson’s disease without the need of having a specialized gait laboratory. This system consists of inertial sensor units attached laterally to both shoes. The computed target of measures are spatiotemporal gait parameters including stride length and time, stance phase time, heel-strike and toe-off angle, toe clearance, and inter-stride variation from gait sequences. To translate this prototype into medical care, we conducted a cross-sectional study including 190 Parkinson’s disease patients and 101 age-matched controls and measured gait characteristics during a 4x10 meter walk at the subjects’ preferred speed. To determine intraindividual changes in gait, we monitored the gait characteristics of 63 patients longitudinally. Cross-sectional analysis revealed distinct spatiotemporal gait parameter differences reflecting typical Parkinson’s disease gait characteristics including short steps, shuffling gait, and postural instability specific for different disease stages and levels of motor impairment. The longitudinal analysis revealed that gait parameters were sensitive to changes by mirroring the progressive nature of Parkinson’s disease and corresponded to physician ratings. Taken together, we successfully show that wearable sensor-based gait analysis reaches clinical applicability providing a high biomechanical resolution for gait impairment in Parkinson’s disease. These data demonstrate the feasibility and applicability of objective wearable sensor-based gait measurement in Parkinson’s disease reaching high technological readiness levels for both, large scale clinical studies and individual patient care.

Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.