Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging.

Background: Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood.

Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging.

Although aging significantly elevates the risk of developing neurodegenerative diseases, how age-related neuroinflammation preconditions the brain toward pathological progression is ill-understood. To comprehend the scope of type I interferon (IFN-I) activity in the aging brain, we surveyed IFN-I-responsive reporter mice and detected age-dependent signal escalation in multiple brain cell types from various regions. Selective ablation of from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain.

Differences in educational opportunity predict white matter development.

Coarse measures of socioeconomic status, such as parental income or parental education, have been linked to differences in white matter development. However, these measures do not provide insight into specific aspects of an individual's environment and how they relate to brain development. On the other hand, educational intervention studies have shown that changes in an individual's educational context can drive measurable changes in their white matter.

Transcriptional Responses of Different Brain Cell Types to Oxygen Decline.

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells.

White matter and literacy: A dynamic system in flux.

Cross-sectional studies have linked differences in white matter tissue properties to reading skills. However, past studies have reported a range of, sometimes conflicting, results. Some studies suggest that white matter properties act as individual-level traits predictive of reading skill, whereas others suggest that reading skill and white matter develop as a function of an individual's educational experience.

Development of the Alpha Rhythm Is Linked to Visual White Matter Pathways and Visual Detection Performance.

Alpha is the strongest electrophysiological rhythm in awake humans at rest. Despite its predominance in the EEG signal, large variations can be observed in alpha properties during development, with an increase in alpha frequency over childhood and adulthood. Here, we tested the hypothesis that these changes in alpha rhythm are related to the maturation of visual white matter pathways.

DLK-MAPK Signaling Coupled with DNA Damage Promotes Intrinsic Neurotoxicity Associated with Non-Mutated Tau.

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3.

Modeling Alzheimer's disease in primary neurons reveals DNA damage response coupled with MAPK-DLK signaling in wild-type tau-induced neurodegeneration.

Background: Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood.

Methods: To model AD-relevant neurodegeneration driven by tau, we overexpressed wild-type human tau in primary mouse neurons and characterized the subsequent cellular and molecular changes.

Groupitizing reflects conceptual developments in math cognition and inequities in math achievement from childhood through adolescence.

Understanding the cognitive processes central to mathematical development is crucial to addressing systemic inequities in math achievement. We investigate the "Groupitizing" ability in 1209 third to eighth graders (mean age at first timepoint = 10.48, 586 girls, 39.

An analysis-ready and quality controlled resource for pediatric brain white-matter research.

We created a set of resources to enable research based on openly-available diffusion MRI (dMRI) data from the Healthy Brain Network (HBN) study. First, we curated the HBN dMRI data (N = 2747) into the Brain Imaging Data Structure and preprocessed it according to best-practices, including denoising and correcting for motion effects, susceptibility-related distortions, and eddy currents. Preprocessed, analysis-ready data was made openly available.

Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques.

The principal signals that drive memory and cognitive impairment in Alzheimer's disease (AD) remain elusive. Here, we revealed brain-wide cellular reactions to type I interferon (IFN-I), an innate immune cytokine aberrantly elicited by amyloid β plaques, and examined their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Using a fate-mapping reporter system to track cellular responses to IFN-I, we detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types.

Evaluating the Reliability of Human Brain White Matter Tractometry.

The validity of research results depends on the reliability of analysis methods. In recent years, there have been concerns about the validity of research that uses diffusion-weighted MRI (dMRI) to understand human brain white matter connections , in part based on the reliability of analysis methods used in this field. We defined and assessed three dimensions of reliability in dMRI-based tractometry, an analysis technique that assesses the physical properties of white matter pathways: (1) reproducibility, (2) test-retest reliability, and (3) robustness.

Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system.

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity.

Antiviral Immune Response in Alzheimer's Disease: Connecting the Dots.

Alzheimer's disease (AD) represents an enormous public health challenge currently and with increasing urgency in the coming decades. Our understanding of the etiology and pathogenesis of AD is rather incomplete, which is manifested in stagnated therapeutic developments. Apart from the well-established Amyloid Hypothesis of AD, gaining traction in recent years is the Pathogen Hypothesis, which postulates a causal role of infectious agents in the development of AD.

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging.

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability.

Testosterone and Adult Neurogenesis.

It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear. There is considerable evidence that steroid hormones modulate various stages of adult neurogenesis, and this review provides a focused summary of the effects of testosterone on adult neurogenesis. Initial evidence came from field studies with birds and wild rodent populations.

Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease.

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid-containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology.

Concurrent cell type-specific isolation and profiling of mouse brains in inflammation and Alzheimer's disease.

Nonneuronal cell types in the CNS are increasingly implicated as critical players in brain health and disease. While gene expression profiling of bulk brain tissue is routinely used to examine alterations in the brain under various conditions, it does not capture changes that occur within single cell types or allow interrogation of crosstalk among cell types. To this end, we have developed a concurrent brain cell type acquisition (CoBrA) methodology, enabling the isolation and profiling of microglia, astrocytes, endothelia, and oligodendrocytes from a single adult mouse forebrain.

Microglial Phagocytosis Assay.

Phagocytosis is essential for microglial clearance of apoptotic cells, extracellular protein aggregates, and infectious bacteria in the central nervous system (CNS). While the preparation of primary microglial culture has been described elsewhere, this protocol describes the microglial phagocytosis experimental procedure and the subsequent measurement of microglial phagocytic ability using fluorescent latex beads or fluorescent amyloid beta 42 (Aβ42) peptides.

Protocol for Primary Microglial Culture Preparation.

Primary microglia, in either mono-culture or co-culture with neurons or astrocytes, are a powerful tool for studying mechanisms underlying microglial inflammatory responses and cell type-specific interactions in the central nervous system (CNS). This protocol provides the details of how to prepare high purity primary microglia from newborn mouse pups. The overall steps include brain cell dissociation, mixed glial cell culture, and microglia isolation.

Seasonal and sex differences in cell proliferation, neurogenesis, and cell death within the dentate gyrus of adult wild-caught meadow voles.

Past research indicates that female meadow voles (Microtus pennsylvanicus) show decreased neurogenesis within the hippocampus during the breeding season relative to the non-breeding season, whereas male voles show no such seasonal changes. We expanded upon these results by quantifying a variety of endogenous cell proliferation and neurogenesis markers in wild-caught voles. Adult male and female voles were captured in the summer (breeding season) or fall (non-breeding season), and blood samples and brain tissue were collected.