The mechanosensitive Piezo1 channel is widely distributed in the central nervous system (CNS), expressed by neurons, astrocytes, oligodendrocytes, microglia, neural stem and progenitor cells, retinal ganglion and photoreceptor cells and, moreover, neurovascular and lymphatic endothelial cells, implicating an important role for the Piezo1 channel in the CNS physiology and disease. Indeed, recent studies have disclosed that the Piezo1 channel plays a vital part in mediating or modulating numerous CNS functions, ranging from brain development, synapse function, neurogenesis, axonal (re)generation, axonal pathfinding, astrocyte-neuron communication, axonal myelination, immune response, brain vasculature modelling to cerebrospinal fluid drainage. There is also increasing evidence to indicate critical engagement of the Piezo1 channel in the pathogenesis and progression of multiple debilitating CNS conditions, exemplified by spinal cord injury, stroke and related ischemia/reperfusion brain damage, neurodegenerative diseases, and age-related macular degeneration. Here, we provide a comprehensive overview of the current understanding and highlight the unanswered questions regarding the roles and mechanisms of the Piezo1 channel in CNS functions and diseases, presenting the Piezo1 channel as an attractive therapeutic target to intervene CNS damage and diseases.

INTRODUCTION:Biomolecular condensates are membraneless organelles functionally involved in diverse processes, including cancer progression. Sequestosome-1 (SQSTM1)/p62 regulates liquid-liquid phase separation to drive biomolecular condensates, while programmed death-ligand 1 (PD-L1) promotes cancer cell growth. Although SQSTM1 has been shown to form condensates with several complexes, its full range of partners remains incompletely characterized. OBJECTIVES:This study aimed to investigate the role of SQSTM1 in mediating PD-L1 condensate formation and its contribution to lung tumorigenesis. METHODS:The SQSTM1-PD-L1 interaction and condensate colocalization were examined by immunoprecipitation and immunofluorescence. Truncated SQSTM1 constructs validate the interacting domain with PD-L1, which is supported by computational AlphaFold3 analysis. We applied 1,6-hexanediol, FDA-approved PD-L1 antibody Atezolizumab, and CRISPR/Cas9-based SQSTM1 knockout to disrupt SQSTM1/PD-L1 biomolecular condensates, along with in vitro and in vivo experiments. The Survivin levels were analyzed using real-time quantitative PCR and immunoblotting. Clinical correlations of SQSTM1 and PD-L1 expression with prognosis were assessed using public datasets. RESULTS:Our research demonstrate that SQSTM1, by its Phox1 and Bem1 (PB1) domain, directly interacts with PD-L1 to facilitate the SQSTM1/PD-L1 biomolecular condensate formation. The formation of SQSTM1/PD-L1 condensates prevents PD-L1 from ubiquitin-proteasome-mediated degradation and stabilizes PD-L1 levels. Deletion of the PB1 domain in SQSTM1 inhibits the formation of PD-L1 biomolecular condensates and induces PD-L1 K48 ubiquitination for protein degradation. Disruption of SQSTM1/PD-L1 condensates with 1,6-hexanediol induces PD-L1 proteolysis and reduces cell viability. Knockout of SQSTM1 disrupts PD-L1 condensate formation, downregulates PD-L1 protein levels, and attenuates tumor growth. Treatment with PD-L1 antibody drug Atezolizumab inhibits SQSTM1/PD-L1 condensates and suppresses tumor formation. Clinically, high SQSTM1 and PD-L1 expression correlated with poor prognosis in lung cancer patients. CONCLUSION:Together, the SQSTM1 directly interacts with non-membrane-associated PD-L1 to drive the formation of SQSTM1/PD-L1 biomolecular condensates, which prevent PD-L1 degradation, promote lung tumorigenesis, and serve as a potential therapeutic target in lung cancers.

Targeted protein degradation has emerged as a transformative therapeutic modality in cancer therapy, enabling the elimination of undruggable proteins and overcoming conventional small-molecule resistance. Therapeutic approaches such as endocytosis-targeting chimera (ENDOTAC) and autophagy-targeting chimera (AUTOTAC) facilitate undruggable protein elimination. Here, functionalized fluorescent nanodiamond-targeting chimera (FND-TAC) reveals therapeutic protein clearance and tumor suppression through ENDOTAC linked to AUTOTAC networks. SQSTM1 is a key autophagy receptor mediating ENDOTAC linked to AUTOTAC for targeting protein degradation and cancer therapy. FND is a nanocarrier with stable fluorescence, enabling real-time tracking of protein degradation and tumorigenesis. Pull-down proteomics and STRING network analyses identified SQSTM1 as a central mediator linking Rab5/Rab7-mediated FND endocytosis through ENDOTAC to AUTOTAC. Rab5/Rab7 ubiquitination, coordinated activation of the SQSTM1 PB1, LIR, and UBA domains, and SQSTM1 S403 phosphorylation through AUTOTAC enabled FND nanoparticulosome formation and subsequent nanoparticulophagy. Moreover, SQSTM1-mediated LAMP1/2 organization linked AUTOTAC to LYTAC for lysosomal targeting. Functionalization with the therapeutic PD-L1 monoclonal antibody atezolizumab (ATZ) to form FND-ATZ demonstrated that ATZ-targeted PD-L1 was delivered to lysosomes for clearance and cancer cell death. Furthermore, FND-ATZ highlighted therapeutic PD-L1 clearance and tumor suppression through ENDOTAC linked to AUTOTAC networks. Real-time observation of FND-TAC reveals that ENDOTAC-AUTOTAC networks mediate therapeutic protein clearance and tumor inhibition.

BackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet the epigenetic mechanisms underlying its pathogenesis remain incompletely understood. Histone crotonylation, a novel post-translational modification, has been implicated in neuroinflammation. However, its role in AD-related cognitive impairment has not been elucidated.MethodsHistone crotonylation was examined in 5xFAD and Aβ42-injected mice. Crotonic acid was administered intracerebroventricular (ICV) to elevate hippocampal histone crotonylation in wild-type mice. Cognitive function was assessed using behavioral tests. Synaptic integrity was evaluated via western blotting and Golgi staining. Microglial activation and co-localization of H3K18cr were determined by immunofluorescence. Transcriptomic analysis identified differentially expressed genes and enriched pathways. The role of signal transducer and activator of transcription 1 (STAT1) was validated in BV2 microglial cells using the STAT1 inhibitor fludarabine.ResultsHippocampal pan-histone H3 crotonylation (H3Kcr) and H3K18cr were significantly upregulated in both 5xFAD and Aβ42-injected mice compared to controls. ICV injection of crotonic acid markedly elevated hippocampal H3Kcr and H3K18cr levels and induced significant cognitive deficits, shown by impaired novel object recognition and fear conditioning performance. Crotonic acid treatment resulted in synaptic dysfunction, including reduced synaptic markers (SYN1, SYT, GluA2, GluN2B) and decreased CA1 dendritic spine density. Crotonic acid also induced microgliosis with elevated Iba1 expression. H3K18cr was specifically upregulated in microglia, with no significant changes observed in neurons or astrocytes. Transcriptomic analysis identified 478 differentially expressed genes enriched predominantly in immune-related pathways, with STAT1 highlighted as a key upstream transcription factor. In BV2 cells, crotonic acid significantly increased total and phosphorylated STAT1 (Tyr701) levels via a JAK1-independent mechanism. Treatment with fludarabine effectively suppressed STAT1 expression and attenuated the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.ConclusionThis study provides the first evidence that elevated microglial H3K18cr contributes to AD-related cognitive impairment by promoting STAT1 expression and subsequent neuroinflammation. These findings identify microglial histone crotonylation as a novel epigenetic mechanism in AD pathogenesis and suggest that targeting the H3K18cr-STAT1 axis may represent a potential therapeutic strategy for AD.

Depression is a prevalent neuropsychiatric disorder with high incidence and causing severe disability, representing a clinically unmet challenge and thus demanding more effective therapeutics. Neuroinflammation in the central nervous system (CNS) is a pathological feature of depression and, with increasing recognition, it is also a critical depression-driving mechanism. In the CNS, the P2X7 receptor for extracellular ATP is expressed in microglia and astrocytes, and acts as a key mediator of neuroinflammation. Besides medicinal chemistry efforts in developing novel CNS-penetrable P2X7 antagonists, there is an increasing interest in exploring natural products as medications for CNS conditions including depression. In this mini-review, we discuss the recent progress in examining the therapeutic potential and mechanisms of compounds from natural products, using rodent models of depression, and revealing P2X7-mediated proinflammatory signaling pathways as an important target for their antidepressant actions.

Intraneuronal accumulation of hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD). Given the significant correlation between tau pathology and memory loss in AD patients, identifying vulnerable brain regions, particularly susceptible neuron types in these regions, will advance our understanding of AD onset and shed light on therapeutic strategies to manage its progression. Immunofluorescent staining was employed to identify the brain regions and neuron types vulnerable to tau pathology in AD. A combination of chemogenetics, electrophysiological recording, in vivo Ca2+ recording, and a modified temporal-order discrimination behavior test was utilized to investigate the toxicity of tau accumulation to susceptible neurons in the dorsal part of the ventral hippocampus. Proteomics, phosphoproteomics, and molecular targeting were used to explore the underlying mechanisms of neuron susceptibility to tau accumulation in AD. The beneficial effects of microtubule affinity regulating kinase 4 (MARK4) knockdown and administration of DEPhosphorylation TArgeting Chimera (DEPTAC) were evaluated in AD mice with tau pathology. In postmortem brains of AD patients, we observed robust accumulation of hyperphosphorylated tau in the anterior hippocampal CA1 region, particularly in its Calbindin1− (Calb1−) neurons, as opposed to the posterior hippocampal CA1 region and Calb1+ neurons. The susceptibility of Calb1− neurons to phospho-tau accumulation was also observed in P301L mice, especially in the dorsal part of ventral (anterior in human) hippocampal CA1 (dvCA1). In P301L mice, dvCA1 displayed distinct protein and phosphorylated protein networks compared with dorsal CA1, accompanied by overactivation of MARK4. Overexpressing human tau in Calb1− neurons in the dvCA1 (dvCA1Calb1− neurons) specifically impairs the temporal-order discrimination of objects. Meanwhile, tau accumulation significantly inhibited the excitability and firing patterns of dvCA1Calb1− neurons associated with temporal-order discrimination. Knocking down MARK4 or reducing hyperphosporylated tau via DEPTAC in P301L mice significantly ameliorated AD-like tau pathology in dvCA1Calb1− neurons and improved temporal-order discrimination of objects. These findings highlight the crucial role of dvCA1Calb1− neurons in the early stage of tau pathology and demonstrate the potential of targeting phosphorylated tau through MARK4 knockdown or DEPTAC administration to counter the vulnerability of dvCA1Calb1− neurons and, consequently, ameliorate episodic memory deficits in AD.

UTX (also known as KDM6A) is a histone H3K27 demethylase that acts as an important tumor regulator. UTX has been reported to participate in genome-wide histone modifications and gene expression in tumorigenesis and its mutations are identified in human cancers. Here, UTX is demonstrated to localize both in the cytoplasm and nucleus, notably, cytoplasmic UTX forms puncta and co-localizes in stress granules (SGs) upon different stresses in vitro. Mechanistically, the TPR domain of UTX plays a critical role in regulating SG disassembly by interacting with G3BP1, the central hub of SG, to disrupt the scaffold network of SG under endoplasmic reticulum stress. Importantly, a clinical UTX mutation, D336G in TPR domain, increases cytoplasmic location of UTX, and stabilizes SG. While UTXD336G promotes, WT UTX or UTXTPR inhibits, cell growth and tumorigenesis by regulating SGs both in vitro and in nude mice, and such regulation is G3BP1 dependent. Together, the results suggest a novel cytoplasmic function of UTX as a negative regulator of SG homeostasis, which is involved in stress and disease states such as tumorigenesis.

Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.

Background Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. Methods We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. Results The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. Conclusion This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. We have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation. Here, we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice. These results suggested DEPTACs as targeted modulators of tau phosphorylation, which hold therapeutic potential for AD and other tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer’s disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

Background Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer’s disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. Methods To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. Results In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. Conclusions Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions. Graphical Abstract

Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. Epidermal growth factor receptor (EGFR) is a key protein that plays crucial roles for tumorigenesis and cancer therapy of lung cancers. Here, we show a carbon-based nanoprobe, nanodiamond (ND), which can be applied for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The optimal fluorescent intensities of ND particles were observed in the human lung cancer cells and nude mice under in vivo imaging system. The fluorescence signal of ND particles can be real-time detected in the xenografted human lung tumor formation of nude mice. Moreover, the ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins of lung cancer cells in vitro and in vivo. ND-Cet treatment increased cellular uptake ability of nanocomposites in the EGFR-expressed cells but not in the EGFR-negative lung cancer cells. Interestingly, single ND-Cet complex can be directly observed on the protein G bead by immunoprecipitation and confocal microscopy. Besides, the EGFR proteins were transported to lysosomes for degradation. Together, this study demonstrates that ND-conjugated Cet can apply for targeting EGFR and monitoring tumorigenesis during lung cancer progression and therapy.

The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5ʹ‐triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In this review, we discuss the role and mechanisms of the P2X7 receptor in mediating neuroinflammation and other pathogenic events in a variety of traumatic CNS damage conditions, which lead to loss of neurological and cognitive functions. We raise the perspective on the steady progress in developing CNS‐penetrant P2X7 receptor‐specific antagonists that leverage the ATP‐P2X7 receptor signaling axis as a potential therapeutic strategy to alleviate traumatic CNS damage and related complications.

Abstract Background Human Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive. Methods Mutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co‐immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor‐erythroid 2–related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti‐oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining. Results Overexpressing P301S decreased the protein levels of post‐synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch‐like ECH‐associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S‐reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin–proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S–KEAP1 interaction at K312 rescued the P301S‐suppressed expression of synaptic proteins and memory deficits with anxiety efficiently. Conclusions P301S‐hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies.

Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer’s disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

Delivery of cells onto subretinal chips for stimulation possess a significant technical challenge. Often, such capabilities are confined by sophisticated laboratory-based commercial instrumentation, which are inherently expensive and equipped with a limited capacity. As a result, exploring new delivery techniques requires an ad hoc approach to suit the requirements of the target deposition method, material(s) and cells under investigation. For the first time, a customised 3D printer, equipped with a microvalve, developed at a low cost, and capable of high resolution placement on a retinal chip is proposed. This allowed the investigation of a pneumatically-driven and microvalve printing technique to deliver cells on a subretinal chip, thus suiting the required resolution and localization of cells. The bioink is coupled with a light-induced collagen photo-crosslinking mechanism. The collagen, mixed with the riboflavin, can be crosslinked after exposure to blue light. The cells printed on the chip remained in the collagen patterns and demonstrated good viability and growth. This technique provided a useful means of delivering cells where high precision, throughput and accuracy is required, such as onto sub-retinal chips.

The transient receptor potential melastatin-related 2 (TRPM2) channel, a reactive oxygen species (ROS)-sensitive cation channel, has been well recognized for being an important and common mechanism that confers the susceptibility to ROS-induced cell death. An elevated level of ROS is a salient feature of ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxia-ischaemia. The TRPM2 channel is expressed in hippocampus, cortex and striatum, the brain regions that are critical for cognitive functions. In this review, we examine the recent studies that combine pharmacological and/or genetic interventions with using in vitro and in vivo models to demonstrate a crucial role of the TRPM2 channel in brain damage by ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxic-ischaemia. We also discuss the current understanding of the underlying TRPM2-dependent cellular and molecular mechanisms. These new findings lead to the hypothesis of targeting the TRPM2 channel as a potential novel therapeutic strategy to alleviate brain damage and cognitive dysfunction caused by these conditions.

Research attention has been given to selective autophagy due to its potential application in the pathophysiology of human diseases. The selective autophagy pathway contributes to the target recognition and degradation of intracellular components or foreign pathogens for maintaining cellular homeostasis in multiple organisms. Notably, this process is mediated by autophagy receptors in the recognition of autophagy cargoes through binding to the ubiquitin-binding domain and LC3-interacting region to the formation of autophagosomes. Nanotechnology is an emerging field; related research has focused on the study and manipulation of nanoscale materials that can be applied for numerous applications, especially for the diagnosis and treatment of human diseases. Nanoparticle-mediated autophagy activation holds promise for use in autophagy-related disease applications. The selective autophagy of nanoparticles and nanodrugs occurs through binding to ubiquitinated proteins, autophagy receptors, and LC3, the formation of nanoparticulosomes, and their delivery to lysosomes; the process is termed nanoparticulophagy. This review focuses on the mechanisms of nanoparticulophagy, the role of selective autophagy receptors, and potential applications in autophagy-related diseases achieved using these nanoparticles and nanodrugs. Nanoparticulophagy will provide an understanding of related intracellular trafficking mechanisms and degradation pathways for processing nanoparticles and nanodrugs in terms of drug delivery and pathophysiological effects.