Jonathan Kipnis

Cerebral amyloid angiopathy (CAA), characterized by cerebrovascular amyloid deposition, is strongly associated with Alzheimer’s disease, ischemic injury, and lobar hemorrhages. APOE4 is the strongest known genetic risk factor for CAA, yet the cellular sources of APOE4 that drive pathogenic vascular amyloid deposition remain poorly defined. Here, we identify vascular-associated fibroblasts (VAFs) as a key source of APOE4 that mediates CAA and cerebrovascular dysfunction. In post-mortem brain tissue from APOE4/E4 patients with confirmed CAA, APOE colocalizes with COL6⁺ VAFs around Aβ-laden vessels. Therefore, to study the contribution of APOE4 derived from VAFs in CAA, independently of parenchymal sources, we used 5xFAD mice in which the endogenous mouse Apoe coding exons are replaced with floxed human APOE4 sequences. This enables selective suppression of APOE4 expression in VAFs upon tamoxifen induction of Col1a2-CreERT ⁺ . APOE4 reduction in VAFs markedly reduced CAA, with the strongest effects observed in leptomeningeal vessels. Additionally, Aβ40, which preferentially associates with vascular amyloid, was significantly reduced in the vascular fraction. VAF APOE4 depletion resulted in fewer small microbleeds and an approximately 50% reduction in parenchymal border macrophages within the leptomeningeal compartment, whereas astrocytic reactivity remained unchanged. Functional assessment using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries. Together, these findings establish VAF-derived APOE4 as a compartment-specific driver of CAA and cerebrovascular dysfunction. One Sentence Summary: Vascular-associated fibroblasts are a major source of pathogenic APOE4 that drives vascular dysfunction in cerebral amyloid angiopathy.

Microglia are regarded as self-maintaining brain parenchymal macrophages without contribution from adult hematopoiesis. While peripheral macrophage engraftment into the brain has been reported, the biological variables governing central nervous system (CNS) macrophage niche access remain unclear. We show that CNS macrophage engraftment depends on (1) the balance between tissue-resident macrophage (TRM) self-renewal, (2) the temporal alignment of niche opening with the availability of engraftment-competent cells and (3) proximity to the vacated niche, rather than prolonged niche vacancy. Fate mapping revealed that monocytes entering the subdural space undergo border-associated macrophage (BAM)-like differentiation, clonal expansion, and transpial migration into the parenchyma, whereas mature BAMs directly repopulate selectively vacated parenchymal niches. We further identified a parenchymal macrophage population with a peripheral BAM-like transcriptional program in aged and neurodegenerative human brains, challenging the dogma of MG-exclusivity. Together, these discoveries provide a predictive framework for understanding macrophage maintenance and replacement, and for developing macrophage-based cellular therapies.

Alzheimer’s disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8⁺ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8⁺ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8⁺ T cell infiltration and glial activation. The remaining CD8⁺ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8⁺ T cell accumulation in the brain and tau-mediated neurodegeneration.

Accumulating evidence demonstrates that the central nervous system (CNS) is not disconnected from the peripheral immune system; however, precisely how the adaptive immune system surveils the CNS remains a critical question. Recent findings reveal that channels between the skull and the dura mater facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow of mice under both homeostatic and disease conditions ^1–6 . Skull bone marrow functions as a source of immune cells for the CNS ⁵ , yet its role in CNS antigen-specific adaptive immune responses remains unclear. Here we identify lymphoid structures within the skull bone marrow, featuring germinal-centre-like formations and containing a distinct population of follicular-helper-like T cells that promote B cell activation and humoral immunity through CD40L, IL-21 and IFNγ signalling. Adaptive immune cells within these skull bone marrow lymphoid structures surveil and respond to CNS-derived antigens and contribute to anti-tumour immune responses in mouse brain cancer models. Together, our findings show that the skull bone marrow is a site of CNS immunosurveillance that may influence immune responses across diverse neurological diseases.

Metastasis remains the leading cause of cancer-related mortality, yet the mechanisms that enable disseminated tumor cells to colonize distant organs remain incompletely understood.1,2 Here, we identify vagal sensory neurons as key facilitators of metastatic outgrowth. Using genetic, pharmacologic, surgical, and tissue-targeted denervation strategies in murine models of metastatic melanoma and breast cancer, we show that depletion of vagal sensory inputs markedly reduces pulmonary colonization. Mechanistically, metastatic cells exploit nerve injury-induced protein 1, NINJ1, to engage vagal afferents and activate a β-catenin-dependent transcriptional program. This interaction increases expression of receptors for growth factors and enables cancer cells to respond to macrophage- and fibroblast-derived trophic signals within the metastatic niche. Unbiased co-immunoprecipitation proteomics revealed that NINJ1 sequesters key components of the β-catenin destruction complex, including DVL1, AXIN1, CK1δ/ε, and CK2. Consequently, the presence of vagal sensory neurons leads to an NINJ1-dependent accumulation of active β-catenin form in cancer cells, while pharmacologic inhibition of β-catenin signaling abolished NINJ1-driven growth factor responsiveness. Together, these findings identify a neuro-metastatic axis in which metastatic cells co-opt a vagal sensory neuron-associated repair program to colonize new tissues. Targeting NINJ1 significantly reduced metastatic outgrowth across multiple cancer models and host backgrounds, indicating a broad therapeutic potential of these findings.

Alzheimer’s disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8 ⁺ cells, CD4 ⁺ T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4 ⁺ T cells while circumventing the need for TCR and peptide–MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4 ⁺ T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4 ⁺ T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque–specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4 ⁺ CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.