Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression.

Microglial CD2AP deficiency exerts protection in an Alzheimer's disease model of amyloidosis.

Background: The CD2-associated protein (CD2AP) was initially identified in peripheral immune cells and regulates cytoskeleton and protein trafficking. Single nucleotide polymorphisms (SNPs) in the CD2AP gene have been associated with Alzheimer's disease (AD). However, the functional role of CD2AP, especially its role in microglia during AD onset, remains elusive.

Benchmarking of a multi-biomarker low-volume panel for Alzheimer's disease and related dementia research.

Introduction: In the research setting, obtaining accurate established biomarker measurements and maximizing use of the precious samples is key. Accurate technologies are available for Alzheimer's disease (AD), but no platform can measure all the established and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA) is a technology that requires 15 µL of sample to measure more than 100 analytes.

Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes.

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation.

TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model.

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels.

A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury.

Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species.

New insights into innate immunity in Alzheimer's disease: from APOE protective variants to therapies.

Recent discoveries of rare variants of human APOE may shed light on novel therapeutic strategies for Alzheimer's disease (AD). Here, we highlight the newly identified protective variant [APOE3 Christchurch (APOE3ch, R136S)] as an example. We summarize human AD and mouse amyloidosis and tauopathy studies from the past 5 years that have been associated with this R136S variant.

Cognitive Effects of Simulated Galactic Cosmic Radiation Are Mediated by ApoE Status, Sex, and Environment in APP Knock-In Mice.

Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.

Failure in a population: Tauopathy disrupts homeostatic set-points in emergent dynamics despite stability in the constituent neurons.

Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity.

Alzheimer's Disease-Related Analytes Amyloid-β and Tau in Perilymph: Correlation With Patient Age and Cognitive Score.

Objective: To describe the collection methods for perilymph fluid biopsy during cochlear implantation, detect levels of amyloid β 42 and 40 (Aβ and Aβ), and total tau (tTau) analytes with a high-precision assay, to compare these levels with patient age and Montreal Cognitive Assessment (MoCA) scores, and explore potential mechanisms and relationships with otic pathology.

Study Design: Prospective study.

Setting: Tertiary referral center.

Multi-peptide characterization of plasma neurofilament light chain in preclinical and mild Alzheimer's disease.

Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.

Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.

Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD.

Insufficient evidence for an association between iatrogenic Alzheimer's disease and cadaveric pituitary-derived growth hormone.

A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary-derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease.

Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.

Introduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.

An emerging role for the gut microbiome in tauopathy.

Tauopathies constitute a group of neurodegenerative diseases characterized by abnormal aggregation of the protein tau, progressive neuronal and synaptic loss, and eventual cognitive and motor impairment. In this review, we will highlight the latest efforts investigating the intricate interplay between the gut microbiome and tauopathies. We discuss the physiological interactions between the microbiome and the brain as well as clinical and experimental evidence that suggests that the presence of tauopathy alters the composition of gut microbiota.

Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals.

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with CN Diagnostics' PrecivityAD test for Aβ42 and Aβ40.