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Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG 1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro . They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

Background Lipid dysregulation is associated with several key characteristics of Alzheimer’s disease (AD), including amyloid-β and tau neuropathology, neurodegeneration, glucose hypometabolism, as well as synaptic and mitochondrial dysfunction. The β-site amyloid precursor protein cleavage enzyme 1 (BACE1) is associated with increased amyloidogenesis, and has been affiliated with diabetes via its role in metabolic regulation. Methods The research presented herein investigates the role of hBACE1 in lipid metabolism and whether specific brain regions show increased vulnerability to lipid dysregulation. By utilising advanced mass spectrometry techniques, a comprehensive, quantitative lipidomics analysis was performed to investigate the phospholipid, sterol, and fatty acid profiles of the brain from the well-known PLB4 hBACE1 knock-in mouse model of AD, which also shows a diabetic phenotype, to provide insight into regional alterations in lipid metabolism. Results Results show extensive region – specific lipid alterations in the PLB4 brain compared to the wild-type, with decreases in the phosphatidylethanolamine content of the cortex and triacylglycerol content of the hippocampus and hypothalamus, but increases in the phosphatidylcholine, phosphatidylinositol, and diacylglycerol content of the hippocampus. Several sterol and fatty acids were also specifically decreased in the PLB4 hippocampus. Conclusion Collectively, the lipid alterations observed in the PLB4 hBACE1 knock-in AD mouse model highlights the regional vulnerability of the brain, in particular the hippocampus and hypothalamus, to lipid dysregulation, hence supports the premise that metabolic abnormalities have a central role in both AD and diabetes.

Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer’s disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n  = 27; non-demented controls, n  = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPτ and Aβ burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD-pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML.

Introduction Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer’s disease (AD) pathologies i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ). Here we investigate the influence of HPτ, Aβ and SVD on WMH severity. Results 36 human post-mortem right fixed cerebral hemispheres (mean age 84.4 ± 7.7 years; male: 16, female: 20) containing varying amounts of AD-pathology (AD: 23, controls: 13) underwent T2- weighted MRI with WMH assessed according to the age related white matter change scale (ARWMC). After dissection, using tissue samples from the frontal, temporal, parietal and occipital regions from the right hemisphere, we quantitatively assessed cortical HPτ and Aβ pathology burden by measuring the percentage area covered by AT8 immunoreactivity (HPτ-IR) and 4G8 immunoreactivity (Aβ-IR), and assessed the severity of WM SVD by calculating the sclerotic index (SI) of WM arteries/arterioles. HPτ-IR, Aβ-IR, and SI were compared with ARWMC scores. HPτ-IR, Aβ-IR and WM ARWMC scores were all significantly higher in AD cases compared to controls, while SI values were similar between groups. ARWMC scores correlated with HPτ-IR, Aβ-IR and SI in various regions, however, linear regression revealed that only HPτ-IR was a significant independent predictor of ARWMC scores. Conclusions Here we have shown that increasing cortical HPτ burden independently predicted the severity of WMH indicating its potentially important role in the pathogenesis of WM damage. Moreover, our findings suggest that in AD patients the presence of WMH may indicate cortical AD-associated pathology rather than SVD. Further studies are warranted to elucidate the pathological processes that lead to WM damage and to clarify if WMH may serve as a general biomarker for cortical AD-associated pathology.

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative dementia, estimated to affect 50 million people worldwide. Despite extensive research into AD, current therapeutic options provide only symptomatic relief, with no disease-modifying treatments presently available, which highlights the need to understand the aetiology of AD. Increasing evidence implicates mitochondrial dysfunction and metabolic deficits in the early stages of AD pathogenesis. In AD, the accumulation of oligomeric amyloid-β (Aβ) within the mitochondria allows it to interact with key mitochondrial proteins, such as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) - a multifunctional protein which can modulate the cellular response to metabolic stress. Levels of 17β-HSD10 are upregulated within several disease-relevant regions of the human brain in AD, and the high affinity interaction between 17β-HSD10 and Aβ has been linked to cellular toxicity. Previous research shows that the catalytic function of 17β-HSD10 is essential to propagate the Aβ-induced toxicity, hence indicating that either inhibiting the enzyme or preventing the interaction between 17β-HSD10 and Aβ may hold potential as a point of therapeutic intervention. Therefore, the primary aim of the research presented within this project was to develop cellular models to advance screening of small molecule inhibitors of 17β-HSD10 developed by the group. HEK293 and differentiated SH-SY5Y cellular models overexpressing 17β-HSD10 showed that the toxicity arising from the protein's interaction with Aβ may selectively impact vulnerable cells with a high metabolic demand. To explore the disease-relevant implications of metabolic deficits within the brain, lipidomics analysis was performed using a murine model of AD and human post mortem AD brain tissue, which revealed an increased susceptibility of the hippocampus to lipid dysregulation, and a potential role for lipid abnormalities in the white matter degeneration observed within the human brain in AD.

Background SIRT1 is likely to play a role in the extension in healthspan induced by dietary restriction. Actions of SIRT1 are pleiotropic, and effects on healthspan may include effects on DNA methylation. Polycomb group protein target genes (PCGTs) are suppressed by epigenetic mechanisms in stem cells, partly through the actions of the polycomb repressive complexes (PRCs), and have been shown previously to correspond with loci particularly susceptible to age-related changes in DNA methylation. We hypothesised that SIRT1 would affect DNA methylation particularly at PCGTs. To map the sites in the genome where SIRT1 affects DNA methylation, we altered SIRT1 expression in human intestinal (Caco-2) and vascular endothelial (HuVEC) cells by transient transfection with an expression construct or with siRNA. DNA was enriched for the methylated fraction then sequenced (HuVEC) or hybridised to a human promoter microarray (Caco-2). Results The profile of genes where SIRT1 manipulation affected DNA methylation was enriched for PCGTs in both cell lines, thus supporting our hypothesis. SIRT1 knockdown affected the mRNA for none of seven PRC components nor for DNMT1 or DNMT3b. We thus find no evidence that SIRT1 affects DNA methylation at PCGTs by affecting the expression of these gene transcripts. EZH2, a component of PRC2 that can affect DNA methylation through association with DNA methyltransferases (DNMTs), did not co-immunoprecipitate with SIRT1, and SIRT1 knockdown did not affect the expression of EZH2 protein. Thus, it is unlikely that the effects of SIRT1 on DNA methylation at PCGTs are mediated through direct intermolecular association with EZH2 or through effects in its expression. Conclusions SIRT1 affects DNA methylation across the genome, but particularly at PCGTs. Although the mechanism through which SIRT1 has these effects is yet to be uncovered, this action is likely to contribute to extended healthspan, for example under conditions of dietary restriction.

The largest cause of cancer-related fatalities worldwide is lung cancer. In its early stages, lung cancer often exhibits no signs or symptoms. Its signs and symptoms often appear when the condition is advanced. The Kirsten rat sarcoma virus oncogene homolog is one of the most frequently mutated oncogenes found in non-small cell lung cancer. Patients who have these mutations may do worse than those who do not, in terms of survival. To understand the nuances in order to choose the best treatment options for each patient, including combination therapy and potential resistance mechanisms, given the quick development of pharmaceuticals, it is necessary to know the factors that might contribute to this disease. It has been observed that single nucleotide polymorphisms altering let-7 micro-RNA might impact cancer propensity. On the other hand, gefitinib fails to stop the oncogenic protein from directly interacting with phosphoinositide3-kinase, which may explain its resistance towards cancer cells. Additionally, Atorvastatin may be able to overpower gefitinib resistance in these cancer cells that have this mutation regardless of the presence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. De novo lipogenesis is also regulated by this virus. To overcome these effects, several targeted therapies have been proposed. One such therapy is to use inhibitors of focal adhesion kinases. When this is inhibited, viral oncogene mutant cancers are effectively stopped because it functions downstream of the virus. Mutant oncoproteins like epidermal growth factor receptor may depend on Heat Shock protein90 chaperones more frequently than they do on natural counterparts that make it more attractive therapeutic target for this virus. Inhibition of the phosphoinositide 3-kinase pathway is frequent in lung cancer, and fabrication of inhibitors against this pathway can also be an effective therapeutic strategy. Blocking programmed cell death ligand1 is another therapy that may help T cells to recognize and eliminate cancerous cells. This homolog is a challenging therapeutic target due to its complex structural makeup and myriad biological characteristics. Thanks to the unrelenting efforts of medical research, with the use of some inhibitors, immunotherapy, and other combination methods, this problem is currently expected to be overcome.

This study compares the hydromorphological quality of two sub-Himalayan Rivers, the Mahananda–Balason system (MBS) and the Chel–Neora system (CNS), to analyse the role of human intervention in channel hydromorphology. An indicator-based assessment, developed by Mitra et al. (Adv Space Res 71:1397–1417, 2022), is adopted here to obtain the hydromorphological quality. A hypothesis test using a two-tailed t-test and principal component analysis (PCA) is performed to identify the reaches with similar hydromorphological conditions along with aspects that needed restoration. Results show that the hydromorphological condition is highly influenced by the intensity of human alterations, and their interrelations are strongly proportionate. While the hydromorphological quality of unconfined MBS is highly degraded, that of unconfined CNS and the confined reaches of both systems have remained almost at their least disturbed condition (LAC). Intensive human interventions on MBS have impacted the groundwater table, riverine sediments, and fish habitat. Now, to maintain sustainability regarding riverine resources of CNS, close and regular monitoring must be initiated, and this methodology can serve that purpose. Being dependent on monitoring the ongoing interventions and the channel's physical forms, assessment protocols like this can serve the purpose of rapid hydromorphological assessment for the river systems of data-scarce regions.

Breast cancer is among the most prevalent forms of cancer. The conventional modalities employed in the management of breast cancer include mainly surgery, radiation, and chemotherapy. The enhanced comprehension of the complex pathobiology of breast cancer has resulted in the emergence of immunotherapy as a highly auspicious therapeutic approach. This is a narrative review focusing on nanotechnology‑enabled immunotherapy strategies for breast cancer, at the interface of tumor immunology and nanomedicine. We highlight lipid nanoparticles, polymeric nanoparticles, inorganic nanomaterials, virus-like particles, and extracellular vesicle-based systems that modulate the anti-tumor immune response. Immunotherapy stimulates the patient's immune system to selectively recognize and eliminate cancerous cells. The present methodology focuses on the primary molecular constituents of neoplastic tissue and offers a potentially novel therapeutic strategy. Comprehending the intricate interplay between neoplastic cells and immunological components is paramount for devising efficacious therapeutic interventions. Immunotherapy can not only eliminate tumors but also be proven effective in impeding metastasis and recurrence. The implementation of immunotherapy in clinical settings has encountered certain constraints, such as weak immune responses resulting from insufficient delivery of immunostimulants to target cells and unregulated modulation of the immune system, leading to the development of autoimmunity and non-specific inflammation. Nanomedicines offer a unique opportunity to maximize the efficacy of immunotherapy and significantly reduce its side effects. The present article discusses the latest developments in breast cancer immunotherapy involving nanotechnology. These advancements encompass a range of approaches, including the direct stimulation of the immune system via the administration of tumor antigens and adjuvants to immune cells, the modification of the tumor microenvironment to reduce immunosuppression, and integration with other therapeutic modalities. We summarise current evidence, identify critical knowledge gaps, and outline future directions for biomarker-guided and combination nano-immunotherapy trials in breast cancer.

Chronic nonhealing wounds remain a major clinical challenge, driven by persistent inflammation, impaired angiogenesis, defective extracellular matrix remodeling, and incomplete functional restoration. While stem cell therapies can modulate these processes, their clinical use is limited by low engraftment, variability, and safety concerns. Stem cell-derived extracellular vesicles (SC-EVs) and artificial nanovesicles (SC-ANVs) have emerged as cell-free alternatives that aim to capture key paracrine functions of stem cells. In this review, we evaluate these vesicle-based approaches within a problem-oriented framework linking molecular and cellular effects to clinically meaningful outcomes. SC-EVs and SC-ANVs influence inflammation, angiogenesis, and tissue regeneration in preclinical wound models; however, current evidence is largely limited to improvements in wound closure and histological parameters. We highlight that proof of concept for clinically relevant endpoints, such as durable function, reduced scarring, and recurrence prevention, remains insufficient. Key translational challenges, including delivery, dosing, and endpoint selection, are discussed, along with a framework for future studies required to establish therapeutic efficacy. Collectively, SC-EVs and SC-ANVs represent emerging platforms whose clinical potential depends on rigorous validation against defined clinical benchmarks.