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Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus—brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively—from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience. Leng et al. uncover the molecular signature of neuronal subpopulations that are selectively vulnerable to tau aggregation and death early in Alzheimer’s disease in the human entorhinal cortex and other brain regions, validating RORB as a marker.

Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18–99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95–1·00] for p-tau217, AUC=0·97 [0·94–0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92–1·00] for p-tau217, AUC=0·91 [0·82–1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91–0·96] for p-tau217, AUC=0·91 [0·88–0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88–0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86–0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

Despite advances towards understanding the molecular pathophysiology of the neurodegenerative dementias, the mechanisms linking molecular changes to neuropathology and neuropathological changes to clinical symptoms remain largely obscure. Connectivity is a distinctive feature of the brain and the integrity of functional network dynamics is crucial for normal functioning. A better understanding of network disruption in the neurodegenerative dementias might help bridge the gap between molecular changes, pathological changes, and symptoms. Recent findings on functional network disruption as assessed with resting-state or intrinsic connectivity functional MRI and electroencephalography and magnetoencephalography have shown distinct patterns of network disruption across the major neurodegenerative diseases. These network abnormalities are somewhat specific to the clinical syndromes and, in Alzheimer's disease and frontotemporal dementia, network disruption tracks the pattern of pathological changes. These findings might have practical implications for diagnostic accuracy, allowing earlier detection of neurodegenerative diseases even at the presymptomatic stage, and tracking of disease progression.

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy. Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits.

The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is not known which dysregulated molecular pathways are primarily responsible for disease initiation or progression. We established an inducible mouse model of poly(GR) toxicity in which (GR)80 gradually accumulates in cortical excitatory neurons. Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral abnormalities, as well as age-dependent neuronal cell loss, microgliosis and DNA damage, probably caused in part by early defects in mitochondrial function. Poly(GR) bound preferentially to the mitochondrial complex V component ATP5A1 and enhanced its ubiquitination and degradation, consistent with reduced ATP5A1 protein level in both (GR)80 mouse neurons and patient brains. Moreover, inducing ectopic Atp5a1 expression in poly(GR)-expressing neurons or reducing poly(GR) level in adult mice after disease onset rescued poly(GR)-induced neurotoxicity. Thus, poly(GR)-induced mitochondrial defects are a major driver of disease initiation in C9ORF72-related ALS/FTD.The authors generated a mouse model of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia based on dipeptide repeat proteins and report that defects in mitochondria may contribute to disease pathogenesis.

Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs) 1 , and recent studies have identified primate-specific neuronal populations at the molecular level 2 . However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution. Evolutionary modelling shows that an initial set of inhibitory neurons serving olfactory bulbs may have been repurposed to diversify the taxonomy of interneurons found in the expanded striata and cortices in primates.

Despite recent advances in fluid biomarker research in Alzheimer’s disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau 275 and MTBR-tau 282 ) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)- MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD- MAPT and AD compared to control and other FTLD-tau (for example, Pick’s disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau 275 and MTBR-tau 282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs. Cerebrospinal fluid measures of isoform-specific tau species from the microtubule-binding region serve as the first fluid biomarkers of primary tauopathy.

Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin 1 , 2 . However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn −/− microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn −/− microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration. In the absence of progranulin, microglia enter a disease-specific state that causes endolysosomal dysfunction and neurodegeneration, and these microglia promote TDP-43 granule formation, nuclear pore defects and cell death specifically in excitatory neurons via the complement activation pathway.

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

Intrinsic or resting state functional connectivity MRI and structural covariance MRI have begun to reveal the adult human brain’s multiple network architectures. How and when these networks emerge during development remains unclear, but understanding ontogeny could shed light on network function and dysfunction. In this study, we applied structural covariance MRI techniques to 300 children in four age categories (early childhood, 5–8 y; late childhood, 8.5–11 y; early adolescence, 12–14 y; late adolescence, 16–18 y) to characterize gray matter structural relationships between cortical nodes that make up large-scale functional networks. Network nodes identified from eight widely replicated functional intrinsic connectivity networks served as seed regions to map whole-brain structural covariance patterns in each age group. In general, structural covariance in the youngest age group was limited to seed and contralateral homologous regions. Networks derived using primary sensory and motor cortex seeds were already well-developed in early childhood but expanded in early adolescence before pruning to a more restricted topology resembling adult intrinsic connectivity network patterns. In contrast, language, social–emotional, and other cognitive networks were relatively undeveloped in younger age groups and showed increasingly distributed topology in older children. The so-called default-mode network provided a notable exception, following a developmental trajectory more similar to the primary sensorimotor systems. Relationships between functional maturation and structural covariance networks topology warrant future exploration.