Citations

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and Trem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.

Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer’s disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood–brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.

Deleting neuronal heparan sulfates in a mouse model of Alzheimer’s disease results in faster Aβ clearance, reduced Aβ aggregation, and less amyloid pathology.

Immunization strategies generating large numbers of antigen-specific T cells in the female reproductive tract (FRT) can provide barrier protection against sexually-transmitted pathogens, such as the human immunodeficiency virus (HIV) and human papillomaviruses (HPV). The kinetics and mechanisms of regulation of vaccine-induced adaptive T cell-mediated immune responses in FRT are less well defined. We present here evidence for intranasal delivery of the model antigen ovalbumin (OVA) along with alpha-galactosylceramide adjuvant as a protein vaccine to induce significantly higher levels of antigen-specific effector and memory CD8+ T cells in the FRT, relative to other systemic and mucosal tissues. Antibody blocking of the CXCR3 receptor significantly reduced antigen-specific CD8+ T cells subsequent to intranasal delivery of the protein vaccine suggesting an important role for the CXCR3 chemokine-receptor signaling for T cell trafficking. Further, intranasal vaccination with an adenoviral vector expressing OVA or HIV-1 envelope was as effective as intramuscular vaccination for generating OVA- or ENV-specific immunity in the FRT. These results support the application of the needle-free intranasal route as a practical approach to delivering protein as well as DNA/virus vector-based vaccines for efficient induction of effector and memory T cell immunity in the FRT.

ObjectiveApolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified.MethodsWe reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE‐targeted replacement (apoE‐TR) mice, which do not show amyloid pathology.ResultsClinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease‐related pathologies. In animal studies, aged apoE2‐TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2‐TR mice showed similar or greater age‐related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3‐TR or apoE4‐TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2‐TR mice had higher apoE levels. Moreover, apoE2‐TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms.InterpretationAPOE2 is associated with less cognitive decline during aging. This can occur independently of age‐related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758–774

Background and Purpose— Age-related changes in the cerebrovasculature, including blood–brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to age-related organ dysfunction, we evaluated whether senescent vascular cells are associated with compromised BBB integrity. Methods— Effects of vascular cell senescence on tight junction and barrier integrity were studied using an in vitro BBB model, composed of endothelial cells, pericytes, and astrocytes. In addition, tight junction coverage in microvessels and BBB integrity in BubR1 hypomorphic (BubR1 H/H ) mice, which display senescence cell-dependent phenotypes, were examined. Results— When an in vitro BBB model was constructed with senescent endothelial cells and pericytes, tight junction structure and barrier integrity (evaluated by transendothelial electric resistance and tracer efflux assay using sodium fluorescein and Evans blue-albumin were significantly impaired. Endothelial cells and pericytes from BubR1 H/H mice had increased senescent-associated β-galactosidase activity and p16 INK4a expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1 H/H mice, consistent with a compromised BBB integrity from permeability assays. Importantly, the coverage of microvessels by end-feet of aquaporin 4–immunoreactive astrocytes was not altered in the cortex of the BubR1 H/H mice. Conclusions— Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB disruption related to biological aging.