Core Viewpoint - Alzheimer's disease (AD) is a severe neurodegenerative disorder with significant impacts on individuals and society, yet drug development has faced numerous failures despite substantial investments from major pharmaceutical companies [2][3]. Drug Development and FDA Approvals - In June 2021, the FDA accelerated the approval of Aducanumab, developed by Eisai and Biogen, marking the first new drug for Alzheimer's since 2003, although its approval was controversial due to associated risks like ARIA (Amyloid-related Imaging Abnormalities) [3][6]. - Following Aducanumab, the FDA approved two additional antibody drugs targeting Aβ: Donanemab by Eli Lilly and Lecanemab by Eisai and Biogen, both of which also present ARIA-related side effects [3][6]. Denali Therapeutics' Research - Denali Therapeutics published a study in August 2025 on a new antibody transport carrier, ATV cisLALA, which utilizes transferrin receptor (TfR) to enhance brain delivery of anti-Aβ antibodies while mitigating ARIA risks [4][9]. - The ATV cisLALA carrier shows improved distribution in brain tissue compared to traditional Aβ antibodies, which tend to accumulate around blood vessels, potentially triggering inflammatory responses and ARIA [9][11]. Mechanism of Action - Traditional Aβ antibodies enter the brain through cerebrospinal fluid and perivascular spaces, where amyloid deposits are located, leading to inflammation and ARIA. In contrast, the ATV carrier enhances delivery through capillaries, reducing ARIA side effects [11][12]. - Denali's TfR-based approach is not limited to Aβ; the company is also developing therapies targeting tau protein using the same delivery mechanism, aiming to address two key toxic proteins in Alzheimer's simultaneously [11].

Core Viewpoint - The research published by Yale University confirms the presence of T cells in the healthy brains of mice and humans, specifically in the subfornical organ (SFO), indicating that T cells can reside in the brain under normal conditions, contrary to previous beliefs about the blood-brain barrier and immune cell isolation [3][11]. Group 1: Research Findings - The study reveals that T cells in the SFO are enriched and play a crucial role in monitoring gut and fat tissue information, which is essential for regulating feeding and behavior [3][11]. - T cells in the SFO are distinct from those in the meninges, as they express proteins like CXCR6 that allow them to remain in brain tissue and secrete immune signaling proteins such as IFNγ [8][11]. - The research indicates a relationship between dietary habits and the quantity of T cells in the brain, with high-fat diets leading to an increase in T cells in both fat tissue and the brain [8][9]. Group 2: Mechanisms of Interaction - The study demonstrates that fasting increases T cell numbers in the brain while decreasing them in fat tissue, suggesting that dietary intake can dynamically regulate T cell migration to the central nervous system [9][11]. - Antibiotic intervention to deplete gut microbiota resulted in a significant reduction of T cells in the brain, indicating that gut microbiota may influence immune cell homeostasis in the central nervous system [9][11]. - The presence of T cells in the brain is linked to feeding behavior, as T cell-deficient mice took longer to find food when hungry compared to normal mice, highlighting their role in foraging and eating behaviors [9][11].

Core Viewpoint - The research reveals the developmental control mechanism of the meningeal lymphatic system in the brain, highlighting the dynamic regulation by neural activity through specific glial cell subtypes, which provides new insights into the interaction between the nervous and immune systems [3][6][9]. Group 1: Research Findings - The study identifies that neural activity regulates the expression of Vegfc in slc6a11b+ radial astrocytes, which in turn controls the development of mural lymphatic endothelial cells (muLEC) in the meninges [3][5]. - It demonstrates that slc6a11b+ radial astrocytes are the primary source of Vegfc, essential for muLEC development, and that this process is modulated by neural activity [7][9]. - The collaboration between slc6a11b+ radial astrocytes and ccbe1+ fibroblasts ensures that muLEC is restricted to the brain surface, preventing invasion into the brain parenchyma [5][9]. Group 2: Implications for Future Research - The findings suggest that the brain not only processes neural information but also coordinates its microenvironment, providing a new framework for understanding brain-immune interactions [9]. - The research opens avenues for interventions targeting this regulatory network, potentially offering new perspectives on the role of the meningeal lymphatic system in neurodegenerative diseases [9][14]. - It emphasizes the importance of a functional lymphatic network for brain health, indicating that targeting the external lymphatic pathways may enhance treatment efficacy for neurological disorders [14].