Explore the vast range of titles available.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD), but its role for disease initiation and progression has remained incompletely understood. We here show that the transcription factor Stat3 (signal transducer and activator of transcription 3), a canonical inducer of astrogliosis, is activated in an AD mouse model and human AD. Therefore, using a conditional knockout approach, we deleted Stat3 specifically in astrocytes in the APP/PS1 model of AD. We found that Stat3‐deficient APP/PS1 mice show decreased β‐amyloid levels and plaque burden. Plaque‐close microglia displayed a more complex morphology, internalized more β‐amyloid, and upregulated amyloid clearance pathways in Stat3‐deficient mice. Moreover, astrocyte‐specific Stat3‐deficient APP/PS1 mice showed decreased pro‐inflammatory cytokine activation and lower dystrophic neurite burden, and were largely protected from cerebral network imbalance. Finally, Stat3 deletion in astrocytes also strongly ameliorated spatial learning and memory decline in APP/PS1 mice. Importantly, these protective effects on network dysfunction and cognition were recapitulated in APP/PS1 mice systemically treated with a preclinical Stat3 inhibitor drug. In summary, our data implicate Stat3‐mediated astrogliosis as an important therapeutic target in AD. Synopsis Modulation of Stat3‐mediated reactive astrogliosis in an Alzheimer's disease mouse model attenuates pathology, enhances amyloid clearance and protects from cognitive decline. These effects are recapitulated in mice treated with a pharmacological Stat3 inhibitor. Generation of a Stat3 (a canonical mediator of reactive astrogliosis) deletion specifically in astrocytes in a mouse model of Alzheimer's disease (AD). Stat3 depletion resulted in strongly attenuated AD‐related pathology, better microglial amyloid clearance, normalization of cerebral network function and a preservation of learning and memory. Protection was recapitulated in AD model mice treated with a pharmacological Stat3 inhibitor, implicating modulation of reactive astrogliosis as a novel treatment target in AD. Graphical Abstract Modulation of Stat3‐mediated reactive astrogliosis in an Alzheimer's disease mouse model attenuates pathology, enhances amyloid clearance and protects from cognitive decline. These effects are recapitulated in mice treated with a pharmacological Stat3 inhibitor.

Cortical spreading depolarization (SD) waves negatively affect neuronal survival and outcome after ischemic stroke. We here aimed to investigate the effects of vagus nerve stimulation (VNS) on SDs in a rat model of focal ischemia. To this end, we delivered non-invasive VNS (nVNS) or invasive VNS (iVNS) during permanent middle cerebral artery occlusion (MCAO), and found that both interventions significantly reduced the frequency of SDs in the cortical peri-infarct area compared to sham VNS, without affecting relative blood flow changes, blood pressure, heart rate or breathing rate. In separate groups of rats subjected to transient MCAO, we found that cortical stroke volume was reduced 72 h after transient MCAO, whereas stroke volume in the basal ganglia remained unchanged. In rats treated with nVNS, motor outcome was improved 2 days after transient MCAO, but was similar to sham VNS animals 3 days after ischemia. We postulate that VNS may be a safe and efficient intervention to reduce the clinical burden of SD waves in stroke and other conditions.

The brain’s network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer’s disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid β—a key culprit in CAA—from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Petzold and colleagues show that serotonergic innervation of the olfactory bulb functions to attenuate odor-evoked transmitter release from olfactory sensory neurons (ORNs). This effect is indirect, as serotonin stimulates 5-HT2C receptors on juxtaglomerular interneurons, whose release of GABA inhibits glutamate release from ORN terminals via GABAB receptors. Centrifugal serotonergic fibers innervate the olfactory bulb, but the importance of these projections for olfactory processing is unclear. We examined serotonergic modulation of sensory input to olfactory glomeruli using mice that express synaptopHluorin in olfactory receptor neurons (ORN). Odor-evoked synaptic input to glomeruli was attenuated by increased serotonin signaling through serotonin 2C (5-HT2C) receptors and amplified by decreased serotonergic activity. Intravital multiphoton calcium imaging revealed that 5-HT2C receptor activation amplified odor-evoked activity in a subset of juxtaglomerular cells and attenuated glutamate release from ORN terminals via GABA B receptors. Endogenous serotonin released by electrical stimulation of the dorsal raphe nucleus attenuated odor-evoked responses without detectable bias in glomerular position or odor identity. Weaker glomerular responses, however, were less sensitive to raphe stimulation than strong responses. Our data indicate that the serotonergic system regulates odor inputs in the olfactory bulb and suggest that behavioral states may alter odor processing at the earliest stages.

Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.

Background Blood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature. Methods We conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed. Results 91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (K trans : 0.55 × 10 − 3 min − 1 ± 0.74 × 10 − 3 min − 1 ) but not the MCI-group (K trans : 0.177 × 10 − 3 min − 1 ± 0.22 × 10 − 3 min − 1 ), compared to the NC group (K trans : 0.19 × 10 − 3 min − 1 ± 0.37 × 10 − 3 min − 1 , p  < .01). sPDGFRβ was not significantly different between the cognitive groups. However, sPDGFRβ levels were significantly associated with age ( r  = .33, p  < .01), independent of vascular risk factors. Further, sPDGFRβ showed significant positive associations with soluble Aβ levels (Aβ40: r  = .57, p  < .01; Aβ42: r  = .39, p  < .01) and YKL-40 ( r  = .53, p  < .01), a marker of neuroinflammation. sPDGFRβ/DCE-MRI was not associated with overall AD biomarker positivity or APOE-status. Conclusion In dementia, but not MCI, hippocampal BBB disruption was observed. sPDGFRβ increased with age and was associated with neuroinflammation independent of cognitive impairment. The association between Aβ and sPDGFRβ may indicate a bidirectional relationship reflecting pericytes’ clearance of soluble Aβ and/or vasculotoxic properties of Aβ.

Neurological post-COVID condition (PCC) often involves attentional deficits that impact daily functioning. Traditional paper-based tests, like the Trail-Making Test (TMT), may inadequately capture these impairments due to their short duration and dependence on numerical and alphabetic sequencing. This study evaluates the validity of three subtests of the computerized Test for Attentional Performance (TAP) as alternatives for detecting attentional impairments in PCC. In the ongoing NEURO LC-19 DE study, 108 subjects aged 18 to 79 years, with PCC-related cognitive complaints ( n  = 67, 73% f) and healthy controls ( n  = 41, 56% f) underwent neuropsychological testing. The prevalence of impairment and classification ability of the TAP subtests were evaluated alongside standard paper-based tests, including the TMT and Montreal Cognitive Assessment, using receiver operating characteristic (ROC) analysis and regression. The TAP subtests identified significant impairments in sustained attention and processing speed in one-third of PCC patients, surpassing traditional tests in sensitivity, and classifying PCC with an AUC of 78%. Omissions in sustained attention significantly differentiated groups (OR = 1.14, p  = 0.016, 95% CI [1.02–1.26]). Fatigue correlated with poorer performance on speed and accuracy ( r  > 0.30, p  < 0.05). Cognitive slowing is prevalent in neurological PCC but is scarcely captured by conventional assessments. The TAP’s computerized format with automated norming and independence from alphanumeric stimuli shows promise in improving the discriminatory ability for identifying attentional deficits in PCC patients.

High-affinity, Na + -dependent glutamate transporters are the primary means by which synaptically released glutamate is removed from the extracellular space. They restrict the spread of glutamate from the synaptic cleft into the perisynaptic space and reduce its spillover to neighboring synapses. Thereby, glutamate uptake increases the spatial precision of synaptic communication. Its dysfunction and the entailing rise of the extracellular glutamate concentration accompanied by an increased spread of glutamate result in a loss of precision and in enhanced excitation, which can eventually lead to neuronal death via excitotoxicity. Efficient glutamate uptake depends on a negative resting membrane potential as well as on the transmembrane gradients of the co-transported ions (Na + , K + , and H + ) and thus on the proper functioning of the Na + /K + -ATPase. Consequently, numerous studies have documented the impact of an energy shortage, as occurring for instance during an ischemic stroke, on glutamate clearance and homeostasis. The observations range from rapid changes in the transport activity to altered expression of glutamate transporters. Notably, while astrocytes account for the majority of glutamate uptake under physiological conditions, they may also become a source of extracellular glutamate elevation during metabolic stress. However, the mechanisms of the latter phenomenon are still under debate. Here, we review the recent literature addressing changes of glutamate uptake and homeostasis triggered by acute metabolic stress, i.e., on a timescale of seconds to minutes.

Cerebral small vessel disease (CSVD) is associated with changes in the retinal vasculature which can be assessed non-invasively with much higher resolution than the cerebral vasculature. To detect changes at a microvascular level, we used optical coherence tomography angiography which resolves retinal and choroidal vasculature. Participants with CSVD and controls were included. White matter lesions were determined on magnetic resonance imaging (MRI). The retinal and choroidal vasculature were quantified using swept-source optical coherence tomography angiography. Data were analysed using linear regression. We included 30 participants (18 females; patients, n  = 20; controls, n  = 10) with a mean age of 61 ± 10 years. Patients had a higher mean white matter lesion index and number of lesions than controls ( p  ≤ 0.002). The intraindividual deviation of choriocapillaris reflectivity differed significantly between age-matched patients (0.234 ± 0.012) and controls (0.247 ± 0.011; p  = 0.029). Skeleton density of the deep retinal capillaries was significantly associated with the number of lesions on MRI (β = − 5.3 × 10 8 , 95%-confidence interval [− 10.3 × 10 8 ; − 0.2 × 10 8 ]) when controlling for age. The choroidal microvasculature and the deep retinal vascular plexus, as quantified by optical coherence tomography angiography, are significantly altered in CSVD. The value of these findings in diagnosing or monitoring CSVD need to be assessed in future studies.