Sensory afferents are increasingly recognized as active participants in tissue homeostasis through interactions with vascular, immune, and parenchymal cells. In ischemic stroke, however, these pathways operate within a broader multicellular pathophysiology that also includes energy failure, excitotoxicity, oxidative stress, blood-brain barrier disruption, systemic immune responses, and multiple regulated cell-death programs [1–4]. This review examines how sensory receptors and neuropeptides may contribute to neuroimmune and metabolic remodeling in ischemic and inflammatory disease. TRPV1 is discussed as one component of a wider transient receptor potential channel network rather than as an exclusive upstream regulator [2, 5]. Substance P (SP) has comparatively direct preclinical support as a mediator of neurogenic inflammation and edema after cerebral ischemia, whereas calcitonin gene-related peptide (CGRP) has context-dependent vascular and immune effects [6, 7]. CGRP-targeted monoclonal antibodies and receptor antagonists are clinically established for migraine, but they have not been validated as stroke treatments; notably, CGRP receptor antagonism worsened ischemic outcomes in a mouse model by impairing collateral perfusion [8–10]. We further review mitochondrial dysfunction, SIRT1/PGC-1α signaling, lipid peroxidation, and ferroptosis as intersecting metabolic processes, while emphasizing that direct causal links from sensory signaling to these pathways in human stroke remain incompletely established [11–14]. The sensory-immune-metabolic framework is best viewed as a hypothesis-generating integrative model embedded within the broader neurovascular unit response to ischemia rather than as a dominant disease driver. Physical neuromodulation and ferroptosis-modulating compounds remain investigational for mechanism-specific stroke prevention. Future work should prioritize causal validation, receptor redundancy, dose and timing effects, translational pharmacology, and biomarker-stratified clinical studies before axis-directed interventions can be considered for routine stroke care.
The aggregation of the microtubule-associated protein tau is a hallmark in many neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Hypertension increases the risk of neurodegenerative diseases, and there is evidence that drugs targeting the renin-angiotensin system (RAS) to reduce blood pressure (BP) could potentially delay neurodegenerative disease onset due to their action on brain RAS. However, the effect of such treatment on pathologies associated with tau are understudied. We have treated three-month old line 66 (L66) tau-transgenic mice expressing the P301S mutation for six weeks with the angiotensin receptor blocker (ARB) candesartan at 5 mg/kg and investigated tau pathology, angiotensin II (Ang II) type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), neurones, microglia, and astrocytes using immunohistochemistry (IHC) and immunoblotting. AT1R and AT2R levels, as well as cortical thickness, number of neurones, GFAP-positive astrocytes and Iba1-positive microglia were all not affected by candesartan treatment. L66 mice had more human tau but less mouse pSer202 tau and total mouse tau, but candesartan treatment did not normalise these differences. Therefore, candesartan administered for six weeks at 5 mg/kg did not lead to a significant reduction of dementia-related pathologies in L66 tau-transgenic mice.
Alzheimer’s disease is a major neurodegenerative disorder in which beta-amyloid (Aβ) proteins, tau pathology, neuroinflammation, and dysfunction of the cholinergic system interact to cause cognitive decline. Although acetylcholinesterase (AChE) has traditionally been viewed as the enzyme responsible for terminating cholinergic signals, growing evidence suggests that it also has non-catalytic interactions with beta-amyloid and tau proteins. It may affect amyloid-related pathways. However, the relative role and mechanistic significance of these non-traditional functions remain incompletely defined. This review summarizes the enzymatic, structural, and signaling roles of acetylcholinesterase in Alzheimer’s disease and examines the evidence linking this enzyme to beta-amyloid protein accumulation, tau pathology, and presenilin-1-associated amyloid processing. We also discuss cholinesterase inhibitors and emerging multi-target strategies, highlighting the distinction between symptom-related cholinergic improvement and potential disease-modifying effects. Overall, the enzyme acetylcholinesterase represents a therapeutically significant target, and its non-stimulatory functions warrant further investigation in experimental and clinical studies.
Prenatal exposure to maternal stress during natural disasters may alter neurodevelopmental trajectories, with long-term impacts for self-regulation. The uncinate fasciculus (UF), a frontolimbic white matter tract central to self-regulation, undergoes protracted maturation during adolescence and may be particularly sensitive to prenatal stress exposure. This study investigated whether Superstorm Sandy (SS, October 2012, New York City) exposure in-utero impacts the relation between adolescent UF development and adolescent emotional-behavioral functioning. Participants (aged 9–14 years; n = 64; 12 SS-exposed) were recruited from the Stress in Pregnancy (SIP) study and underwent diffusion MRI. Parents reported children’s externalizing and internalizing problems (CBCL), and behavioral and emotional regulation (BRIEF-2). General linear models tested associations between SS-related stress exposure and UF fractional anisotropy (FA), and emotional-behavioral functioning. We further examined whether prenatal stress exposure mediated/moderated associations between UF FA and emotional-behavioral functioning. All models adjusted for age, sex, and handedness and were corrected for multiple comparisons (FDR-adj. p < 0.15). Prenatal stress exposure was not associated with adolescent UF FA or emotional-behavioral functioning. While mediation effects were not observed, significant interaction effects were observed and indicated that prenatal SS-related stress exposure moderated the association between bilateral UF FA and adolescent behavioral and emotional regulation; higher UF FA was associated with better emotional-behavioral functioning. Of note, this association was significantly stronger among SS-exposed adolescents compared to their unexposed peers. These findings suggest that prenatal disaster-related stress exposure moderates the association between frontolimbic white matter development and adolescent emotional-behavioral functioning, highlighting MRI of UF as a potential imaging marker of adaptive capacity. Clinical trial number: Not applicable.
Cerebral amyloid angiopathy–related inflammation (CAA-RI) and primary angiitis of the central nervous system (PACNS) are rare inflammatory cerebrovascular disorders that frequently present with overlapping clinical, radiological, and laboratory features. Despite similarities, they differ substantially in pathophysiology, diagnosis, treatment, and outcomes, making their distinction a major clinical challenge critical for management. This paper compares their pathophysiology, clinical manifestations, diagnostics, therapeutics, and prognosis, while highlighting diagnostic dilemmas and future research priorities. A literature review examined immunopathogenesis, neuroimaging, cerebrospinal fluid (CSF) biomarkers, histopathology, treatments, and outcomes, emphasizing overlap and divergence. CAA-RI is characterized by an autoimmune inflammatory response against amyloid-β–laden cerebral vessels, producing perivascular inflammation, blood–brain barrier dysfunction, and vasogenic edema. PACNS, conversely, is an idiopathic vasculitis driven by adaptive immune mechanisms without vascular amyloid deposition. Clinically, both may present with cognitive impairment, headache, seizures, focal deficits, and encephalopathy. However, CAA-RI typically affects older individuals and is more strongly associated with cerebral microbleeds, cortical superficial siderosis, and asymmetric white matter hyperintensities on MRI. PACNS more commonly demonstrates multifocal ischemic lesions and angiographic vessel irregularity. CSF anti-amyloid-β autoantibodies, reduced CSF amyloid levels, and APOE ε4 homozygosity are promising CAA-RI biomarkers, whereas PACNS lacks disease-specific markers. Brain biopsy remains the gold standard but is increasingly reserved for cases of uncertainty. High-dose corticosteroids are first-line therapy, with additional immunosuppressants for refractory or relapsing disease. Compared with PACNS, CAA-RI generally shows lower relapse rates and more favorable functional outcomes. Despite overlap, distinctions in immunopathology, imaging, biomarkers, and prognosis enable differentiation through a multimodal diagnostic approach.
