Background: Amyloid beta (Aβ) which is recognized as a main feature of Alzheimer’s disease (AD) has been proposed to “spread” through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied. Methods: To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP). Results: It is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway. Conclusions: Our findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.

Despite the increasing number of anti-hypertensive drugs have been developed and used in the clinical setting, persistent deficiencies persist, including issues such as lifelong dosage, combination therapy. Notwithstanding receiving the treatment under enduring these deficiencies, approximately 4 in 5 patients still fail to achieve reliable blood pressure (BP) control. The application of neuromodulation in the context of hypertension presents a pioneering strategy for addressing this condition, con-currently implying a potential central nervous mechanism underlying hypertension onset. We hypothesize that neurological networks, an essential component of maintaining appropriate neurological function, are involved in hypertension. Drawing on both peer-reviewed research and our laboratory investigations, we endeavor to investigate the underlying neural mechanisms involved in hypertension by identifying a close relationship between its onset of hypertension and an excitation and inhibition (E/I) imbalance. In addition to the involvement of excitatory glutamatergic and GABAergic inhibitory system, the pathogenesis of hypertension is also associated with Voltage-gated sodium channels (VGSCs, Nav)-mediated E/I balance. The overloading of glutamate or enhancement of glutamate receptors may be attributed to the E/I imbalance, ultimately triggering hypertension. GABA loss and GABA receptor dysfunction have also proven to be involved. Furthermore, we have identified that abnormalities in sodium channel expression and function alter neural excitability, thereby disturbing E/I balance and potentially serving as a mechanism underlying hypertension. These insights are expected to furnish potential strategies for the advancement of innovative anti-hypertensive therapies and a meaningful reference for the exploration of central nervous system (CNS) targets of anti-hypertensives.

In this editorial, we critically evaluate the recent article by Niu et al , which explores the potential of phospholipase D2 (PLD2) as a biomarker for stratifying disease severity in acute pancreatitis (AP). AP is a clinically heterogeneous inflammatory condition that requires reliable biomarkers for early and accurate classification of disease severity. PLD2, an essential regulator of neutrophil migration and inflammatory responses, has emerged as a promising candidate. Although current biomarkers such as C-reactive protein and procalcitonin provide general indications of inflammation, they lack specificity regarding the molecular mechanisms underlying AP progression. Recent studies, including the research conducted by Niu et al , suggest an inverse correlation between PLD2 expression and AP severity, offering both diagnostic insights and mechanistic understanding. This editorial critically evaluates the role of PLD2 as a biomarker in the broader context of AP research. Evidence indicates that decreased levels of PLD2 are associated with increased neutrophil chemotaxis and cytokine release, contributing to pancreatic and systemic inflammation. However, several challenges remain, including the need for large-scale validation and functional studies to establish causation, and standardization of measurement protocols. Additionally, further investigation into the temporal dynamics of PLD2 expression and its variability across diverse populations is warranted. Looking ahead, PLD2 holds the potential to revolutionize AP management by integrating molecular diagnostics with precision medicine. The utilization of large-scale multi-omics approaches and advancements in diagnostic platforms could position PLD2 as a fundamental biomarker for early diagnosis, prognosis, and potentially therapeutic targeting. While promising, it is crucial to conduct critical evaluations and rigorous validations of PLD2’s role to ensure its efficacy in improving patient outcomes.

As societies age, the global prevalence of dementia is expected to reach 139 million by 2050, with an estimated cost of $2.8 trillion by 2030 alone. However, dementia is neither an inevitable nor an unavoidable condition, up to 40% of cases can be prevented or delayed by addressing established risk factors (Long et al., 2023). Neurovascular health plays a pivotal role in the etiology, progression, and outcomes of neurocognitive decline. Impaired neurovascular coupling, characterized by reduced endothelial vasodilatory capacity (Rudnicka-Drożak et al., 2022) and diminished oxygen and glucose delivery to neurons due to decreased cerebral blood flow (Kisler et al., 2017), has been implicated in the onset and progression of dementia. Understanding the intricate interplay between vascular factors and neurodegenerative mechanisms is crucial for addressing the global burden of cognitive disorders. Advancing our understanding of neurovascular health brings us closer to mitigating cognitive decline through early detection, targeted interventions, and personalized care.Cerebral small vessel disease (CSVD) is increasingly acknowledged as a critical contributor to neurocognitive decline, particularly in aging populations. From 2008 to 2030, nearly 5000 publications on CSVD have appeared in 790 journals across 84 countries. Yan et al. (10.3389/fnagi.2024.1400844) conducted a bibliometric analysis and network visualizations of these literatures, providing insights into future research prospects. Their analysis identified magnetic resonance imaging (MRI) segmentation and enlarged perivascular spaces in the Basal ganglia as recent research interest, based on keywords co-occurrence analysis and burst graph emergence detection. MRI segmentation may enhance the diagnostic capabilities for CSVD and inspire the exploration of therapeutic targets. However, the diagnostic significance of enlarged perivascular spaces in CSVD remains unrecognized, necessitating further research into lesion differentiation and the development of quantitative methods to assess disease burden accurately.Leveraging on its high spatial resolution, MRI uniquely visualizes subtle brain changes associated with neurocognitive decline. It is revealing that alterations in white matter integrity and cortical thinning, are crucial for understanding early-stage cognitive impairment due to vascular pathology. By integrating structural and functional imaging techniques, MRI provides a comprehensive understanding of how vascular risk factors contribute to neurocognitive decline. This facilitates the identification of biomarkers for early intervention before dementia. Zhang et al. (10.3389/fnagi.2023.1278390) reviewed advancements in multimode MRI, including structural MRI (sMRI), diffusion tensor imaging, resting-state fMRI, and magnetic resonance spectroscopy, in assessing vascular cognitive impairment not dementia (VCIND). They concluded that MRI not only elucidate the neurobiological mechanisms of vascular cognitive impairment (VCI) but also aids in distinguishing VCI from VCIND. Unlike MRI, Li et al. (10.3389/fnagi.2024.1364808) found EEG, featured by high temporal resolution, offers more precision in discriminating VCIND from healthy controls. They also demonstrated that combining EEG and sMRI using machine learning outperformed unimodal approaches in differentiating various stages of VCI. Their research highlights the possibility for early clinical diagnosis of VCI, enabling timely intervention that may delay or even reverse neurocognitive decline (Gorelick et al., 2011).To gain deeper insight into vascular contributions to neurocognitive decline, Lim et al. (10.3389/fnagi.2024.1430408) examined clinical cases of post-stroke cognitive decline, focusing on brain structure, function, and metabolism. This 6-year study analyzed multimodal MRI and 18Fflorbetaben PET data from 11 post-stroke cognitive decline and 10 matched non-decline controls. However, no difference was observed between the two groups on the CVSD features, including the proportion of moderate-to-severe white matter hyperintensities (WMHs) as well as the number of lacunes and microbleeds. In the decliner group, WMH volume showed a marked association with neurocognitive scores. A similar phenomenon occurred in amyloid PET characteristics, where subthreshold PET standardized uptake value ratios negatively correlated with both final neurocognitive scores and changes over time. WMH-induced white matter tract damage and amyloid pathology lead to neural network deficits that eventually trigger neurocognitive decline (Coenen et al., 2023), consistent with their study. These findings hint that neurovascular involvement in neurocognitive decline may result from multiple interacting factors.Despite early CVSD lesions, especially before the neurocognitive decline onset, which may be evident on imaging, these changes always lag behind neurovascular lesions. Beyond imaging techniques, emerging biomarkers offer a foundation for assessing the risk and progression of neurocognitive decline. Wang et al. (10.3389/fnagi.2024.1334011) explored the association between C677T polymorphism and neurocognitive decline in a cross-sectional study. C677T mutation is a key enzyme in homocysteine metabolism, causing high homocysteine levels, a known contributor to neurovascular injury (Hassan et al., 2004). Their study found C677T polymorphism as a genetic marker linked to elevated homocysteine levels, aggravating white matter damage and neurocognitive decline in CSVD. Likewise, Wang and Zhang et al. (10.3389/fnagi.2023.1278730) explored insulin resistance as a potential mechanism underlying neurocognitive decline, highlighting its role as another contributor to neurovascular injury. They demonstrated the relationship between the triglyceride-glucose index and neurocognitive decline, emphasizing its utility as a metabolic risk indicator. Moreover, Zhao et al. (10.3389/fnagi.2025.1427737) confirmed...