Buntanetap is an orally available small RNA targeting molecule that inhibits the translation of multiple neurotoxic aggregating proteins, including amyloid precursor protein (APP) and Tau. It has been evaluated in 13 clinical trials involving over 1000 participants, including healthy volunteers, patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD), and has shown a favorable safety and tolerability profile. In two small studies in early AD, buntanetap demonstrated a trend toward cognitive improvement, despite being underpowered for efficacy. In a Phase2/3 study in early PD, it also improved PD patients’ cognitive functions. We evaluated safety and efficacy of buntanetap in treating mild to moderate AD patients in this 3-month randomized double-blind dose-ranging study (NCT05686044). Total of 351 Patients were equally randomized to either 7.5 mg, 15 mg, 30 mg buntanetap or placebo. Buntanetap had a favorable safety profile. The study did not meet its primary endpoints (ADAS-Cog-11 and ADCS-CGIC), as 40% of participants lacked amyloid pathology. However, in amyloid biomarker-positive mild AD patients, buntanetap demonstrated nominally statistically significant dose-dependent cognitive benefits, supported by biomarker evidence of target and pathway engagement. Further evaluation of buntanetap in this patient population are warranted. A Phase 3 trial is currently underway to confirm these findings (NCT06709014).

Abstract Introduction Apolipoprotein E ε4 (E4) is the most potent genetic risk factor for Alzheimer's disease (AD), present in up to 60% of AD patients. Concurrently, sleep impairment is a causal contributor to AD pathogenesis, initiating a vicious, bidirectional feedback loop with β-amyloid (Aβ) pathology that E4 appears to amplify. E4 carriers face elevated risk of amyloid-related imaging abnormalities (ARIA) during Aβ-clearing therapies, underscoring an urgent need for E4-specific, ARIA-sparing therapeutic strategies. We hypothesized that E4 exacerbates amyloid-induced sleep impairments by synergizing with oligomeric Aβ species and driving premature circuit dysfunction. Methods We crossed APPswe/PS1dE9 (APP) transgenic mice with human APOE knock-in mice, establishing E3/APP and E4/APP experimental lines. Sleep microarchitecture, specifically cortical slow oscillation (SO, < 1 Hz) power and propagation, was assessed using in vivo widefield voltage-sensitive dye (VSD) imaging under anesthesia. Sleep macroarchitecture, specifically sleep stage duration and fragmentation, was monitored in non-anesthetized, freely-moving mice using wireless, fully implantable EEG/EMG telemetry. The effect of CN-105, an APOE-mimetic peptide, on sleep and SO was examined. Results E4/APP mice exhibited profound sleep deficits compared to E3/APP controls at 2 months of age, prior to significant plaque deposition. VSD imaging revealed that E4/APP mice exhibited reduced SO power and impaired intra- and interhemispheric functional connectivity. This 2-month onset is dramatically accelerated, as APP mice lacking human APOE did not show SO impairments until 3 months, and E4-only mice were unimpaired at 2 months. Telemetry recordings showed that 2-month-old E4/APP mice displayed significantly reduced NREM sleep, increased wakefulness, and greater sleep fragmentation compared to E3/APP counterparts. Acute 1.5-day treatment with CN-105 rescued micro- and macroarchitectural deficits, restoring SO power and increasing NREM sleep duration in E4/APP mice. Conclusion The E4 genotype functions as an active and reversible driver of sleep impairment, synergizing with oligomeric Aβ species to accelerate the collapse of sleep-regulating neural circuits. The acute rescue of these deficits with CN-105 demonstrates that this E4-driven circuit dysfunction is an active, ongoing process and not yet a permanent structural failure. These findings validate sleep as an important modifiable risk factor in E4 carriers, offering a promising disease-modifying strategy. Support (if any) Cure Alzheimer’s Fund

Traumatic brain injury (TBI) presents a major biomedical challenge due to its complex biomechanics and the heterogeneous cellular responses it elicits, including neuronal death, glial activation, and blood–brain barrier disruption. Traditional in vitro models, including 2D neuronal cultures, brain slices and transwell systems, have provided valuable insights into molecular and cellular biology but remain limited by their lack of human-specific architecture, vascularization, and neurovascular interactions. The purpose of this review is to systematically examine advances in in vitro TBI modeling, with particular attention to studies leveraging human induced pluripotent stem cell (iPSC)-derived neural and vascular tissues, organoids, hydrogel scaffolds, microfluidic platforms, and mechanical injury. We highlight how the integration of neurovascular unit (NVU) components has improved the physiological and functional relevance of these models. Finally, we identify key limitations, including variability in organoid maturation, incomplete vascularization, and lack of methodological standardization, and outline future directions for improving translational fidelity. Therefore, this review contributes to a critical evaluation of emerging technologies and their potential to advance neurotrauma research and therapeutic discovery.

Immunotherapies remain largely ineffective against intracranial malignancies such as glioblastoma (GBM), in part due to profound systemic and local immune dysfunction. Hallmarks of systemic immune dysfunction include bone marrow T cell sequestration, T cell dysfunction, lymphoid organ atrophy, and lymphopenia. We report that intracranial tumors, unlike their extracranial counterparts, induce chronic sympathetic hyperactivity and significantly elevate circulating catecholamine levels in both mice and human patients. In murine models, we demonstrate that intracranial tumors elicit elevated systemic catecholamine levels that result in systemic immune suppression, including impaired T cell function, lymphoid organ atrophy, bone marrow T cell sequestration, and lymphopenia. Interestingly, we also identified these phenomena amidst acute intracranial pathologies, such as stroke and traumatic brain injury. Mice harboring these intracranial pathologies also suffer immune disturbances within the thymus and bone marrow, leading to defective T- and B-cell lymphogenesis. Catecholamines act on the alpha- and beta-adrenergic receptors, which can be found on immune cells. We found that beta-agonism suppresses T cell function, while nonspecific beta-blockade with propranolol restores T cell function and favorably alters the tumor microenvironment (TME). Beta-blockade also significantly improves survival in GBM-bearing mice when combined with 4-1BB agonist and PD-1 blockade immunotherapy. Extended survival is likewise observed in retrospective analysis of nearly 9,000 GBM patients who received beta-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received beta-blockade alongside concomitant immune checkpoint inhibition. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors and advance a role for beta-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.

Objective:To evaluate the effect of non-cardiac/non-neurologic surgery on the CSF proteome, and the effect of the APOE mimetic peptide CN-105 on postoperative CSF proteome changes. Methods:We performed mass spectrometry-based proteomics on preoperative and 24 hour postoperative cerebrospinal fluid (CSF) samples from 137 patients (age>60) in the MARBLE trial (ct.gov identifier: NCT03802396), who were randomized to receive APOE mimetic peptide CN-105 (or placebo), and in an independent replication cohort. Linear regression was used to evaluate postoperative changes in CSF protein levels and pathway scores (measured by single-sample gene set enrichment analysis [ssGSEA]), with false discovery rate (FDR)-based multiple comparison correction. Results:Among 2,086 proteins, 881 (42.2%) showed a change after surgery (p-FDR<0.05), of which 57 proteins (6.4%) showed a log2 fold change >0.5 or <-0.5, and postoperative changes occurred in 1,001 (54.0%) of 1854 pathways (p-FDR<0.05). Similar temporal effects were seen in the majority of these proteins and pathways in the replication cohort. The 5 most significantly upregulated CSF pathways involved smooth muscle cell migration (and its regulation) or apoptotic signaling and regulation (including within endothelial cells). The 5 most significantly downregulated CSF pathways included non-canonical NF-κB signal transduction regulation, leukocyte apoptotic process (and negative regulation of it), and sulfur and proteoglycan metabolic processes. There was no significant CN-105 effect on 24-hour postoperative changes in CSF protein levels or ssGSEA pathway scores (p-FDR>0.05 for all). Conclusions:Significant postoperative changes occurred in over 40% of proteins and over 50% of pathways in the CSF, most significantly in smooth muscle, endothelial, leukocyte, and apoptosis pathways.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in patients with atrial fibrillation (AF); however, inappropriate dosages may increase risk for adverse events. Using data from the American Heart Association’s Get with the Guidelines-Stroke registry (GWTG-Stroke) linked with Medicare data, we evaluated the association of DOAC dosing with risk of stroke/systemic embolism, major bleeding, and all-cause mortality in older ischemic stroke patients with AF. Methods: We included ischemic stroke patients admitted to a GWTG-Stroke hospitals in Oct. 2012-Dec. 2019 who were > 66 years, had a history of AF/flutter, and were discharged on a DOAC (dabigatran, rivaroxaban, or apixaban). DOAC dosing was defined as appropriate (standard dose or appropriately adjusted dose), underdose (reduced dose without indications for dose reduction or dose lower than recommended), or overdose (standard dose in patients with indications for dose reduction or dose higher than recommended). Normalized inverse probability weighted generalized boosted models were used to estimate 1-year outcomes after discharge. Results: Of the 37,464 ischemic stroke survivors (median age: 81 years; 53% female; 7% non-Hispanic Black), 68% were discharged with the appropriate DOAC dose, 22% were underdosed and 10% were overdosed. Apixaban was the most common DOAC (68%), followed by rivaroxaban (23%) and dabigatran (9%). The cumulative 1-year incidence of stroke/systemic embolism were 7.1%, 7.0%, and 7.9% among patients who were appropriate dosed, underdosed, and overdosed. After multivariable adjustments, there was no significant association between DOAC dose and stroke/systemic embolism ( Table ). However, patients who were overdosed (aHR 1.11 [1.01-1.23]) were associated with greater risk of major bleeding compared with appropriately dosed patients. Furthermore, patients who were underdosed were associated with greater risk of all-cause mortality (aHR 1.12 [1.06-1.18]). No significant association with mortality risk was observed in those who were overdosed. Conclusion: In a nationwide registry of ischemic stroke survivors with AF, approximately one-third of patients were prescribed a non-recommended DOAC dose. Patients who were overdosed had greater risk of major bleeding, while those underdosed had a greater risk of all-cause mortality. Strategies, including medical education, to ensure appropriate DOAC dosing at discharge are needed to reduce risk of adverse outcomes.