Microglial activation is a determining factor that allows amyloid-beta accumulation to drive reactive astrogliosis, amplifying inflammatory responses in the brain. This was the conclusion of a study conducted by researchers in Brazil, Canada, and the US.
When microglia are not activated, amyloid stops correlating with elevated plasma levels of glial fibrillary acidic protein (GFAP), indicating that the inflammatory process triggers the cascade of Alzheimer’s disease (AD).
The authors further demonstrated that the microglial-astroglial pathway amplifies tau phosphorylation and contributes to the accumulation of neurofibrillary tangles. These findings reinforce the notion that neuroinflammation is critical for disease progression.
AD is defined by amyloid-beta and tau deposits; however, there is a growing consensus that these proteinopathies alone do not explain clinical heterogeneity. Individuals with similar amyloid burdens can follow radically different trajectories. Recent studies suggest that microglia and astroglia play key roles in this divergence.
In experimental models, activated microglia release cytokines such as interleukin-1 alpha, TNF, and C1q, which can induce neurotoxic reactive astrogliosis. Reactive astroglia also organize around plaques, follow the topography of amyloid-beta, and amplify tau phosphorylation. However, it remains unclear whether microglia modulate the extent to which amyloids drive astroglial activation in humans. To date, this hypothesis has been supported only by experimental or neuropathological evidence.
To address this question, the researchers evaluated 101 participants aged ≥ 50 years from the Canadian Translational Biomarkers of Aging and Dementia (TRIAD) cohort. All patients underwent plasma analyses of p-tau217 and GFAP, as well as PET imaging of amyloid-beta, translocator protein (TSPO), and tau. The sample included individuals with normal cognition, mild cognitive impairment, and dementia associated with AD.
A second sample of 251 participants from the Wisconsin Registry for Alzheimer’s Prevention and TRIAD cohorts were used to validate the findings using soluble TREM2 (sTREM2), a biomarker of microglial activation in the cerebrospinal fluid. All data were analyzed using regression analysis adjusted for age, sex, and cognitive status, as well as interaction models, regional analyses, and structural equation modeling.
The investigators also incorporated postmortem transcriptome data from the Allen Human Brain Atlas, allowing the evaluation of whether the anatomical distribution of TSPO expression correlates with in vivo amyloid-beta glial interactions.
The central finding was that amyloid-beta was associated with increased GFAP only when microglia were activated. Among individuals with microglial activation, a higher amyloid load was strongly correlated with plasma GFAP levels, whereas in those without activation, this relationship disappeared completely. The interaction between amyloid-beta and TSPO outperformed any model without interaction, and the result was replicated using sTREM2. Amyloid alone is insufficient to induce reactive astrogliosis, and microglial activation determines this outcome.
Brain region analyses showed that the association between amyloid-beta and GFAP in individuals with microglial activation was concentrated in the frontal, parietal, temporal, and cingulate cortices, which are the brain regions most vulnerable to AD. Notably, the areas where amyloid-beta and microglia interacted to increase GFAP levels corresponded to the cortical regions with the highest physiological TSPO expression in the Allen Human Brain Atlas. This topographic correspondence suggests that the basal molecular architecture of the brain helps define the most pronounced amyloid-beta glial interface.
Researchers have also demonstrated that microglial-astroglial signals are directly related to pathological tau. GFAP was associated with p-tau217 and PET detected tau only when microglial activation was present, indicating that neuroinflammation is not merely a late response but an intermediate step in the transition from soluble to aggregated tau.
Structural modeling showed that the amyloid-beta → GFAP → p-tau217 → tau PET → cognition pathway accounted for 76% of the cognitive variability but only in individuals with activated microglia. In the absence of microglial activation, the chain was incomplete, and amyloid-beta did not exert a meaningful effect on cognition.
These findings clearly reposition neuroinflammation within the AD cascade.
A 2015 study described close interactions between microglia, astrocytes, and neurons in patients with AD. By placing microglia and astroglia at the center of clinical progression rather than at the margins, this study provides a proof-of-concept in humans.
The inflammatory axis, defined by activated microglia, modulates the timing and location of amyloid deposition, which is biologically relevant for the induction of astrogliosis. These results reinforce the evidence that astrogliosis arises early and may function as a precursor to tauopathy, and that the amyloid-beta → astroglia → tau pathway critically depends on microglial activation.
From a biomarker perspective, this study strengthens the role of plasma GFAP as a practical indicator of amyloid-associated astrogliosis.
In a cross-sectional analysis of more than 300 individuals across the AD continuum, researchers showed that plasma GFAP increases in both preclinical and symptomatic phases, shows greater alterations than CSF GFAP, and better discriminates amyloid-beta-positive from amyloid-beta-negative individuals, including those in the early stages of the disease.
By demonstrating that the association between amyloid-beta and GFAP depends on microglial activation, the current study helps clarify these findings: Plasma GFAP is not simply a marker of nonspecific damage but also a sensitive indicator of amyloid-linked glial neuroinflammation, with direct implications for trial enrolment and monitoring.
Conceptually, these findings support the expansion of the framework to include an inflammatory glial component, given that the chronology and intensity of neuroinflammation modulate the risk for clinical progression in amyloid-beta-positive individuals. Glial markers included YKL 40, MCP 1, GFAP, and sTREM2.
These results provide empirical evidence that amyloid-beta microglial astroglia interactions explain a meaningful proportion of the cognitive variance, supporting the use of these biomarkers for risk stratification and therapeutic design.
Interventions aimed at reducing the formation of A1 astrocytes or restoring synaptic support have shown neuroprotective benefits in tauopathy models.
In this context, the results suggest that anti-amyloid-beta treatments may be more effective when combined with strategies that modulate the glial response, particularly in individuals showing evidence of hyperreactive microglia and astroglia.
Selecting individuals based on a high-risk glial profile, defined, for example, by elevated plasma GFAP levels together with markers of microglial activation, may increase the likelihood of detecting clinical effects in phase 3 trials.
In summary, the AD cascade resembles a less rigid amyloid-beta → tau → cognitive impairment sequence and a network in which microglia and astroglia function as obligatory amplifiers between amyloid deposition and clinical manifestations.
This scenario has two clinical implications: First, it reinforces the importance of incorporating glial biomarkers into research and, potentially, clinical practice. It also opens up a therapeutic pathway beyond plaque removal, targeting neuron-glial interactions to slow disease progression.
Future trials should evaluate microglial modulators, cytokine-specific blockers, and interventions aimed at reactive astrocytes. Longitudinal studies are essential to define the temporality of microglial-astroglial tau interactions and identify therapeutic windows.
Daniela Barros is a journalist with postgraduate training in social journalism from the Pontifical Catholic University of São Paulo, São Paulo, Brazil. She is a special student in the Department of Social Medicine at Ribeirão Preto Medical School, University of São Paulo, São Paulo.
This story was translated from Medscape’s Portuguese edition.
Summary: New research shows that blood from older animals can speed up Alzheimer’s-related changes in the brain, while young blood may slow them down. In a long-term experiment, mice engineered to develop Alzheimer’s symptoms received weekly blood infusions from either young or old donors.
Older blood increased amyloid buildup and worsened cognitive performance, while young blood appeared to have protective effects. Proteomic analysis revealed more than 250 altered proteins linked to synaptic signaling, calcium channels, and other pathways tied to neurodegeneration. The findings highlight circulating blood factors as potential targets for future Alzheimer’s therapies.
Key Facts
Source: Melisa Institute
Alzheimer’s disease is the most common form of dementia worldwide and continues to be one of the greatest public health challenges.
New research, published in the journal Aging-US, reveals that blood from aged mice can accelerate the progression of the disease, while young blood may have protective effects.
The study was led by researchers from Instituto Latinoamericano de Salud Cerebral (BrainLat) at Universidad Adolfo Ibáñez in conjunction with MELISA Institute, the University of Texas Health Science Center at Houston, and Universidad Mayor.
Alzheimer’s is characterized by the abnormal accumulation of beta-amyloid protein (Aβ) in the brain, forming plaques that disrupt communication between neurons and generate neurodegenerative processes.
Although this protein originates in the central nervous system, recent studies have suggested that it may also be present in the blood, opening new possibilities for understanding how the disease progresses.
To explore this hypothesis, the team used Tg2576 transgenic mice (a model widely used in Alzheimer’s research), which received weekly blood infusions from young and old mice for 30 weeks to assess whether factors present in the blood could modulate amyloid accumulation and the animals’ behavior.
“This collaborative work between various institutions reinforces the importance of understanding how systemic factors condition the brain environment and directly impact mechanisms that promote disease progression.
By demonstrating that peripheral signals derived from aged blood can modulate central processes in the pathophysiology of Alzheimer’s, these findings open new opportunities to study therapeutic targets aimed at the blood-brain axis,” explained Dr. Claudia Durán-Aniotz, from the Instituto Latinoamericano de Salud Cerebral (BrainLat) at Universidad Adolfo Ibáñez.
The team assessed cognitive performance using the Barnes test, the accumulation of amyloid plaques with histological and biochemical techniques, and performed a comprehensive proteomic analysis of the treated brains.
This analysis revealed more than 250 differentially expressed proteins, linked to synaptic functions, endocannabinoid signaling, and calcium channels, which could explain the observed changes.
Regarding MELISA Institute’s participation in this research, Mauricio Hernández, a proteomics expert at the research and biotechnology center, commented that “within this study, we conducted a large-scale proteomic analysis that allowed us to generate excellent quality data in this complex matrix like plasma, a technical challenge for any proteomics laboratory. Thanks to our state-of-the-art equipment (timsTOF Pro2), we are proud to have contributed to the production of a robust and high-quality scientific article.”
These results reinforce the idea that circulating factors in the blood can directly influence the progression of neurodegenerative diseases such as Alzheimer’s. Understanding these mechanisms will allow for the identification of new therapeutic targets and preventative strategies. The next step will be to determine exactly what these factors are and whether it is possible to intervene in them in humans.
“It is a pleasure to contribute our proteomic capabilities to support innovative research initiatives like this study, which allow us to advance the knowledge and development of new therapies for neurodegenerative diseases, which are currently a global health problem,” emphasized Dr. Elard Koch, Chairman of MELISA Institute.
Funding:
C.DA. was supported by ANID/FONDECYT Regular 1210622, ANID/PIA/ANILLOS ACT210096, the Alzheimer’s Association (AARGD-24-1310017), ANID/FOVI240065 and ANID/Proyecto Exploracion 13240170 and MULTI-PARTNER CONSORTIUM TO EXPAND DEMENTIA RESEARCH IN LATIN AMERICA (ReDLat), supported by NIH research grant R01AG057234 funded by the National Institute of Aging (NIA) and the Fogarty International Center (FIC), an Alzheimer’s Association grant (SG-20-725707-ReDLat), the Rainwater Charitable Foundation, and the Global Brain Health Institute with additional support from the Bluefield Project to Cure Frontotemporal Dementia, an NIH contract (75NS95022C00031), and NIA under awards R01AG075775, R01AG082056, and R01AG083799.
The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health, the Alzheimer’s Association, Rainwater Charitable Foundation, Bluefield Project to Cure Frontotemporal Dementia, or the Global Brain Health Institute.
The contribution of RM and team in this work was supported by NIH grants RF1AG072491 and RF1AG059321. UW was supported by ANID/FONDECYT Regular 1240176.
A: Mice that received blood from older donors showed faster amyloid plaque accumulation, altered brain protein profiles, and worse performance on cognitive tests. These changes suggest that circulating factors in aged blood actively promote processes linked to Alzheimer’s progression.
A: Young blood shifted brain protein expression toward patterns associated with healthier synaptic signaling and reduced disease-related dysfunction. These protective effects point to specific molecular factors that may slow or counteract neurodegeneration.
A: The findings reveal that the blood–brain axis plays a meaningful role in driving or slowing Alzheimer’s progression. Identifying the exact blood-borne molecules involved could lead to new therapeutic targets or preventative strategies aimed at modifying systemic factors rather than the brain alone.
Author: Damian Vallejos
Source: Melisa Institute
Contact: Damian Vallejos – Melisa Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Infusion of blood from young and old mice modulates amyloid pathology” by Claudia Durán-Aniotz et al. Aging-US
Background and aim: The FT4/FT3 ratio reflects thyroid hormone metabolism and has emerged as a prognostic marker in cardiovascular diseases. However, its role in ischemic stroke (IS) remains unclear. This study aimed to investigate the association between the FT4/FT3 ratio and 3-month functional outcomes in IS patients.
Methods: We conducted a retrospective cohort study of 199 first-episode IS patients admitted within 14 days of onset between June 2021 and June 2023. Serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were evaluated upon admission. Neurological severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcomes were evaluated using the modified Rankin Scale (mRS) at 3 months post-stroke. Poor outcome was defined as an mRS score of 3-5. Separate analyses were conducted according to FT4/FT3 ratio and outcome.
Results: Patients were stratified by median FT4/FT3 ratio (3.75) into low (≤ 3.75, n = 100) and high (> 3.75, n = 99) ratio groups. The high-ratio group had lower FT3 (4.14 ± 0.52 vs. 4.68 ± 0.52 pg/mL, p < 0.001), higher FT4 (17.83 ± 2.10 vs. 15.36 ± 1.69 pmol/L, p < 0.001), more diabetes (52.5% vs. 34%, p = 0.010), and higher proportion of poor outcomes (46.5% vs. 28%, p = 0.007). Receiver operating characteristic (ROC) analysis revealed that the FT4/FT3 ratio demonstrated the highest predictive ability (area under the curve [AUC] = 0.662) with an optimal cut-off of 3.845. After adjusting for NIHSS scores, age, sex, and vascular risks, the FT4/FT3 ratio remained an independent predictor of poor outcomes (odds ratio [OR] = 2.589, 95% confidence interval [CI]: 1.171 - 5.727, p = 0.019). FT4 was a risk factor (OR = 1.324, 95% CI: 1.045 - 1.678, p = 0.020), while FT3 showed a nonsignificant protective trend (OR = 0.551, 95% CI: 0.218 - 1.390, p = 0.207).
Conclusion: An elevated FT4/FT3 ratio may serve as a novel biomarker for predicting poor outcomes in ischemic stroke(Do we now tell patients they are going to have a poor outcome?), reflecting thyroid hormone metabolic dysfunction that potentially exacerbates inflammation and impairs neuronal repair.
Limitations: This study is limited by its small sample size, single-center design, and absence of serial hormone measurements.
Doctors at Tallaght University Hospital diagnosed 18 young people with a neurological disorder caused by inhaling nitrous oxide, or ‘laughing gas’, during a recent 20-month period.
The patients attended the hospital’s emergency department suffering from myeloneuropathy, a condition caused by damage to both the spinal cord and peripheral nerves.
They noted that many of the patients were using larger 580g or 640g canisters of nitrous oxide, rather than 8g ‘whippets’ that had originally been popular in the recreational setting.
Some of those admitted to the hospital reported using laughing gas for years, while others told doctors that it was their first time.
The median length of stay at Tallaght University Hospital for the 18 patients was eight days, but discharge was delayed in some cases where patients required intensive rehabilitation due to 'significant functional disability'. File photo: Sasko Lazarov / RollingNews.ie
One said they had consumed 14 canisters a day for three weeks, while another had ‘binged’ six 580g canisters prior to admission.
Nearly all of the patients complained of a numb or tingling sensation on the skin, while 13 reported limb weakness, and eight were observed to have gait impairment.
The median length of hospital stay for the 18 patients was eight days, but discharge was delayed in some cases where patients required intensive rehabilitation due to “significant functional disability”.
Nitrous oxide can cause inactivation of vitamin B12 in the body, which in turn causes damage or loss of the protective layer around nerve fibres in the dorsal spinal column. Three of the patients had taken multivitamins or injected vitamin B12 in a bid to prevent this from happening.
All of the 18 patients who presented with these symptoms between October 2022 and July 2024 were treated with a high dose of vitamin B12 replacement, which the doctors said prevented life-changing disability in a cohort of previously healthy individuals.
“From a public health perspective, this case series demonstrates that nitrous oxide abuse remains a persistent source of concern for physicians and public health bodies in Ireland, despite repeated efforts at public education,” they wrote.
The authors of the study, published in the Irish Journal of Medical Science, said nitrous oxide poses a challenge from a legislative perspective, as it is used without restriction in the catering industry and can be imported for this purpose.
Low-protein, high-fat eating patterns were consistently linked to poor sleep, while low-carb, high-fat diets were tied to reduced short sleep, regardless of blood-sugar status. The findings highlight the need to integrate dietary strategies with sleep-health recommendations.
Key Facts
Source: George Mason University
The average adult should get a minimum of seven hours of sleep daily, according to Centers for Disease Control and Prevention recommendations.
An estimated 50 to 70 million Americans are diagnosed with a sleep disorder (ex., sleep apnea, insomnia) that prevents optimal sleep outcomes, and what we eat may play a role.
A study by registered dietitian and clinical nutrition researcher Raedeh Basiri showed that blood sugar levels—whether in individuals with or without diabetes—are linked to sleep quality.
The research found that blood glucose patterns, diabetes management, and the types of foods people eat all were associated with how well they sleep:
Basiri’s research highlights the importance of considering both dietary patterns and blood sugar status when developing strategies to improve sleep.
A: Fluctuations in blood glucose were strongly linked to sleep problems, with individuals experiencing disrupted glucose patterns reporting more sleep disturbances and irregular sleep duration. This pattern was especially pronounced in individuals with diabetes.
A: Low-protein, high-fat diets were consistently tied to poorer sleep outcomes across participants, regardless of diabetes status. These patterns were linked to reduced sleep quality and more sleep complaints.
A: Yes. Low-carb, high-fat diets were associated with a lower likelihood of short sleepduration in both individuals with diabetes and those with normal glucose levels. This suggests that macronutrient balance may help support healthier sleep.
Author: Mary Cunningham
Source: George Mason University
Contact: Mary Cunningham – George Mason University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Glycemic status and macronutrient intake as predictors of sleep outcomes: an analysis of NHANES 2007–2020 data” by Raedeh Basiri et al. Frontiers in Nutrition
Neuromuscular impairments following ankle sprains are central to chronic ankle instability (CAI), potentially leading to compensatory muscle co-contraction to regulate ankle stiffness, particularly in response to external perturbations. The acute effect of practice on muscle activation and postural responses reveal initial deficits in motor control and indicate the capacity of individuals with CAI to overcome these deficits within their specific constraints. This study aimed to examine adaptive changes in lower limb muscle co-contraction between CAI and healthy control (HC) participants during repeated perturbations and assess whether practice influences postural control and strategy.
Twenty-three CAI and 23 HC participants performed a single-leg balance task involving repetitive mediolateral perturbations. Surface electromyography, ground reaction force and whole-body kinematics were recorded, and margin of stability (MoS) and the coupling between MoS and ankle-/ hip-joint torques were calculated.(I always failed the single leg standing test in the Berg Balance scale. Of course, my physical therapist was useless in addressing the problem, did absolutely nothing about it! But I was tested on a weekly basis, what amazing incompetence displayed!)
Individuals with CAI demonstrated different adaptive changes in muscle co-contraction for Tibialis Anterior (TA) - Peroneus Longus (PL) and TA - Soleus compared to HC. In healthy controls, TA-PL co-contraction decreased significantly with practice, while no changes were observed in the CAI group. Repeated perturbations improved MoS and MoS-Hip torque coordination in CAI, suggesting improved postural control and hip strategy.
Rehabilitation for CAI should target both the whole-body coordination and ankle adaptation exercise since ankle joint appears refractory to change in CAI individuals. Future research should explore whether co-contraction patterns influence risk of ankle sprain in CAI populations, linking lab-based performance to real-world injury risks.
The datasets analysed during the current study are available from the corresponding author (XX) on reasonable request.
