Current Alzheimer Research - Online First

Neurodegenerative diseases comprise a heterogeneous group of disorders characterized by the progressive structural and functional deterioration of neurons in the central nervous system. Among them, Alzheimer’s disease is the most prevalent worldwide. Despite their distinct clinical manifestations, many neurodegenerative disorders share convergent pathophysiological mechanisms such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, which ultimately drive neuronal loss. These processes lead to profound impairments in cognitive performance, motor coordination, and overall functional capacity, making such diseases exceptionally difficult to diagnose early and manage effectively. Traditional treatment approaches administered orally or parenterally face limitations, including high hepatic metabolism, poor penetration across the blood–brain barrier (BBB), and systemic side effects. This review highlights the potential of the nose-to-brain (N2B) delivery system as an emerging and promising therapeutic strategy. N2B delivery utilizes the olfactory and trigeminal nerve pathways in the nasal cavity to rapidly and precisely deliver drugs to the central nervous system without crossing the blood–brain barrier. Because the system is non-invasive, it offers high bioavailability, reduced systemic exposure, and improved patient compliance. The use of lipid nanocarriers, nanoparticles, dendrimers, and nanogels to enhance the stability of drugs, facilitating efficient targeting and controlled release, is a crucial factor in optimizing N2B drug delivery systems. Various attributes influence drug transport, which are physiological, physicochemical and formulation-dependent characteristics. The main challenges faced by the N2B delivery system are enzymatic degradation and mucociliary clearance. Emerging technologies, such as AI, 3D Printing, and personalized medicine, all hold promise for future inventions in this area. Preclinical and clinical trials demonstrate the efficacy of delivering N2B in treating neurodegenerative diseases; however, its full potential remains to be seen due to regulatory, safety, and scalability concerns. Hence, this review emphasizes the research required to pursue interdisciplinary collaboration and unlock the full potential of N2B delivery, as well as a new approach to transforming neurodegenerative conditions.

Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients’ care and clinical success.

Alzheimer's disease is a neurodegenerative disorder characterized by impairments in cognitive functions such as thinking, behavior, and memory. The major pathological abnormalities associated with the disease include the formation of neurofibrillary tangles and amyloid plaques, which further cause neuroinflammation and nerve cell death. Currently, treatments for the disease focus on symptomatic management rather than addressing the root cause of neurological changes. Therefore, the current status of therapy highlights the need for more effective therapeutic substances that can either prevent abnormal deposition or slow neurodegeneration to preserve nerve cells. In this respect, ATP-sensitive potassium channel openers may have a potential role in prevention and protection. The present article focuses on several cellular mechanisms of this class, including the limitation of neuronal excitability, modulation of neurotransmitter release, prevention of aberrant protein buildup, reduction of excessive calcium influx, reduction of reactive oxygen species levels, and reduction of microglial activation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormalities in protein metabolism leading to the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau protein). While these pathological constructs have held significant attention for decades, emerging evidence highlights the understanding of neuroinflammation (notably involving microglia, and cytokine signaling) as a critical initial event with respect to the inception and progression of AD. This review discusses the dynamic and dualistic effects of immune response in AD based on the relationship between neuroinflammatory processes and classical neuropathological characteristics. Microglia are ubiquitous immune cells in the central nervous system responsible for maintaining homeostasis as the brain's “housekeepers” by removing cellular debris, pruning synapses, and monitoring cell interactions. However, microglia in AD function produce a chronically activated phenotype that elicits neurotoxicity, impairs synaptic functioning, and is are protracted source of neuroinflammation. The appearance of disease-associated microglia (DAM) may illustrate complexities of TREM2 signaling for the anabolism of Aβ clearance and the modulation of inflammatory systems. Cytokine imbalance - higher expression of pro-inflammatory (e.g., IL-1β, TNF-α) and lower expression of anti-inflammatory (e.g., IL-10, TGF-β) - adds to a self-perpetuating inflammatory loop that exacerbates Aβ and tau pathology, brain-blood barrier permeability, and peripheral-CNS immune communications. The mechanisms of an inflammatory event may drive brain tau hyperphosphorylation, tau propagation, along with other pathophysiological neurodegenerative features of traumatic brain injury and Alzheimer's disease. While examples of therapies targeting microglia and their cytokine activity are actively being explored, clinical efforts have been mixed. Neuroimaging development (e.g., TSPO-PET), cytokine collection and compositional approaches, and application of single-cell transcriptomics are providing new ways of thinking about complex neuroimmunology. Exploring, informing, and defining the timing, context, and variations of neuroinflammatory responses will be ultimately needed to create effective, targeted therapies for Alzheimer's disease (AD).

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.

A serine/threonine kinase with a wide variety of substrates, Glycogen Synthase Kinase-3 (GSK-3) is widely expressed. GSK-3 is a key player in cell metabolism and signaling, modulating numerous cellular functions and playing significant roles in both healthy and diseased states. The two histopathological features of Alzheimer's disease, the intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and the extracellular senile plaques composed of beta-amyloid, have been linked to GSK-3. It alters multiple tau protein locations found in neurofibrillary tangles. Additionally, GSK-3 can react to this peptide and regulate the production of beta-amyloid. The overexpression of GSK-3 in several transgenic models has been linked to tau hyperphosphorylation, neuronal death, and a reduction in cognitive function. It has been shown that lithium, a medication commonly used to treat affective disorders, inhibits at therapeutically relevant concentrations and stops tau phosphorylation. In this review, we provide an overview of the most recent research on the potential of GSK-3 inhibitors for treating Alzheimer's disease.