Contribution of G4 Structure to Alzheimer’s Disease and Tau Pathology

HMGB1 signalling in Alzheimer's disease: pathogenic roles and therapeutic prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the gradual loss of neurons, especially in the hippocampus and cerebral cortex. This neuronal loss results in cognitive decline, memory problems, and changes in behaviour. It accounts for roughly 90% of all cases, making it the most common reason for dementia worldwide, with a marked rise in its occurrence as one ages. AD is pathologically marked by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and the formation of extracellular amyloid-β plaques. Along with these defining characteristics, oxidative stress and chronic neuroinflammation, which are triggered by prolonged astrocyte and microglia activation and excessive reactive oxygen species production, play crucial roles in the development of the illness. The majority of cases of AD are sporadic late-onset illness, but the less common familial variant is linked to mutations in the APP, PSEN1, and PSEN2 genes that cause aberrant amyloid-β formation. High mobility group box 1 (HMGB1) is a crucial modulator of neuroinflammation in AD, according to new research. By activating the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), HMGB1, especially in its pro-inflammatory disulfide state, hinders memory and learning. RAGE/CaMKKβ-AMPK, ERK1/2, GSK-3β, NF-κB, MAPKs, and NLRP3 inflammasome cascades are among the overlapping downstream signalling pathways that these receptors initiate. Together, these pathways induce tau hyperphosphorylation, amyloid-β buildup, and persistent inflammatory responses. Therefore, a viable treatment approach for reducing neuroinflammation and associated pathologies with AD. is to target HMGB1-mediated signalling networks.

Investigating the role of EFhd2 protein in modulating tau pathology in a tauopathy mouse model

Accumulation of abnormally aggregated tau is the main pathological hallmark in tauopathies, including Alzheimer’s disease (AD). Increasing evidence suggests that pretangle oligomeric tau aggregates exert neurotoxicity, while neurofibrillary tangles (NFTs) may represent less toxic structures that possibly delay cellular demise. A multitude of in vitro studies have endorsed the low propensity of tau protein to aggregate without an external aggregation inducer. Hence, studying tau-interacting proteins has garnered research attention in the last decade as potential contributors to pathological tau aggregation. We identified EF-Hand Domain Family Member D2 (EFhd2) protein as a tau-associated protein in JNPL3 mouse model and postmortem tauopathies tissues. Recently, we have shown that EFhd2 interacts with tau filaments in vitro, promoting the formation of large unique aggregated structures. Based on these findings and others, we hypothesized that EFhd2 might contribute to the formation of tau aggregates in vivo. To test this hypothesis, we examined the impact of deleting the Efhd2 gene on the progressive pathological phenotype and neuropathological changes in TauP301L-expressing mice. The results indicated only modest, sex-specific differences in lifespan associated with Efhd2 deletion in TauP301L mice. Independent of p-values, Efhd2 deletion also showed a medium-to-large main effect in reducing cortical pSer422 and PHF1 tau levels in aged mice, consistent with attenuated late-stage tau aggregation. Moreover, Efhd2 deletion showed effect-size–based trends toward higher Alz50 staining, suggesting an increase in early pathological tau conformations. These findings indicate that Efhd2 deletion is associated with a shift in tau species toward earlier conformational states alongside reduced markers of later-stage aggregation. The observed modest effects do not establish a direct mechanistic role for EFhd2 in tau aggregation in vivo. Rather, they suggest that EFhd2 may function as a modulatory component within a broader protein network influencing tau pathology. Future studies will determine to the extent to which these effects arise from direct modulation of tau aggregation, altered cellular pathways, or interactions within the EFhd2-associated protein network.

Tau dysfunction in alzheimer’s disease: molecular and cellular mechanisms, genetic modulation, and therapeutic perspectives

Mechanisms and Intervention Strategies of Beta-Amyloid and Tau Proteins in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a major threat to the health and quality of life of the aging population worldwide, with its complex and multifactorial pathological mechanisms remaining incompletely elucidated. Mounting evidence indicates that amyloid-beta (Aβ) deposition and tau hyperphosphorylation are not independent events but interact synergistically to drive the onset and progression of AD, creating a self-amplifying pathological cascade. This paper firstly systematically summarizes the biological properties of Aβ and tau proteins, and further explores their synergistic interaction modes and pathogenic effects in the AD pathological cascade. Furthermore, it reviews the latest advances and clinical challenges in targeted therapeutic strategies against Aβ and tau, including antibody-based therapies, small-molecule inhibitors, and gene-targeted interventions. The purpose of this study is to clarify the synergistic pathological network between Aβ and tau, summarize updated progress on targeted therapies, and offer theoretical support for accurate early diagnosis and individualized clinical treatment of AD.

Multi Target Directed Ligand for Alzheimer’s Disease: A Review of Therapeutic Strategies and Advances

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory loss, resulting from various pathological processes such as amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, cholinergic dysfunction, and metal ion imbalance. Current treatments, like acetylcholinesterase inhibitors and NMDA receptor antagonists, only help with the symptoms and don't change how the disease gets worse. The fact that AD has many causes shows how important it is to come up with new ways to treat it. Multi-target directed ligands (MTDLs) have become a promising approach in the last few years. They are meant to work on several important molecular targets that are thought to play a role in the development of Alzheimer's disease. This review summarises progress in the creation and design of MTDLs. It talks about hybrid molecules (like tacrine–chromene derivatives), peptide-based scaffolds, flavonoid conjugates, dual GSK-3β/tau aggregation inhibitors, and new PDE- and AChE-targeting compounds. Compared to regular polypharmacy, MTDLs have more benefits, such as better effectiveness, less toxicity, better compliance, and better pharmacological profiles. Recent advances in medicinal chemistry and structure-based design bolster the argument for MTDLs as next-generation therapeutic candidates, notwithstanding challenges like bioavailability and blood–brain barrier penetration. Ongoing enhancement of these compounds may eventually yield disease-modifying therapies that can impede or avert the advancement of Alzheimer's disease.

The molecular and genetic view of tauopathies: From structural polymorphism to systemic neurodegeneration

Tauopathies constitute a broad group of clinically heterogeneous neurodegenerative disorders, including Alzheimer’s disease, progressive supranuclear palsy, and Pick’s disease, characterized by abnormal metabolism, misfolding, and intracellular aggregation of the microtubule-associated protein tau. These diseases are defined by disruptions in alternative splicing of the tau protein, toxic post-translational modifications such as hyperphosphorylation and acetylation, and the “prion-like” spread of pathological tau seeds across anatomically connected regions. Recent cryogenic electron microscopy studies have demonstrated that each tauopathy has a unique filament-folding structure, elucidating the molecular basis of phenotypic variation among diseases. The aim of this review is to provide a holistic perspective by synthesizing recent developments in the molecular and genetic architecture of tauopathies, particularly newly discovered genetic risk loci and cellular proteostasis mechanisms. In this context, detailing the process from the physiological functions of the tau protein to its pathological transformation aims to analytically evaluate the diagnostic value of fluid biomarkers and current data on next-generation clinical-stage therapeutic strategies, such as monoclonal antibodies and antisense oligonucleotides.