CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Online First

Persistent swelling in the brain, internal tau bundles, and external Amyloid-Beta (Aβ) deposits are characteristics of Alzheimer's Disease (AD), an ongoing neurodegenerative illness. Microglia are the main immune cells in the CNS (Central Nervous System). They keep the brain stable by keeping an eye on the immune system and removing apoptotic cells and protein clusters through a process called phagocytosis. However, in AD, microglia exhibit dysregulated phagocytic activity, resulting in either insufficient Aβ clearance or exacerbated inflammatory responses, both of which contribute to neurodegeneration. This review examines key molecular pathways, such as those mediated by TREM2 (Triggering Receptor Expressed on Myeloid cells), APOE (Apolipoprotein E), and CD33 (Cluster of Differentiation), that govern microglial activation and influence their neuroprotective or neurotoxic functions. We further explore therapeutic strategies to modulate microglial phagocytosis, pharmacological agents (such as minocycline, pioglitazone, rifampicin, etc.), some natural agents, gene-editing tools, and nanomedicine, which aim to optimise microglial response and reduce the neuroinflammatory burden in AD. Despite promising advances, challenges persist in achieving targeted, effective modulation of microglial function due to microglial heterogeneity, limited model fidelity, and potential off-target effects. This review underscores the importance of refining microglia-targeted interventions and developing combinatory approaches that enhance microglial homeostasis to mitigate AD pathology and progression.

The normal cellular prion protein (PrP^C) can misfold into an infectious and pathogenic form (PrP^Sc) to produce prion diseases, also known as transmissible spongiform encephalopathies (TSEs), which are rare and deadly neurodegenerative conditions. The conversion of PrP^C to PrP^𝑆𝑐, which builds up as toxic aggregates in the central nervous system, is caused by sporadic, inherited, or acquired pathways. PrP^Sc-induced proteostasis failure, oxidative stress, neuronal toxicity, and progressive neurodegeneration are characteristics of pathogenesis. Due to their overlap with other neurodegenerative illnesses, prion diseases are still difficult to diagnose, even with breakthroughs in our knowledge of the molecular causes. Cerebrospinal fluid biomarkers, neuroimaging, EEG, and genetic testing are utilized in the diagnostic process. Methods like real-time quaking-induced conversion (RT-QuIC) provide high sensitivity. As there are currently no cures, the main goals of management are palliative care and symptom alleviation. Research is currently being conducted on experimental strategies that target PrP misfolding. These strategies include autophagy enhancers, monoclonal antibodies, antisense oligonucleotides, and small compounds. Artificial intelligence (AI) shows revolutionary promise by enhancing early diagnosis through biomarker analysis, neuroimaging interpretation, and EEG pattern identification. AI also improves clinical trial design, identifies tailored treatment approaches, and accelerates drug discovery. Furthermore, advancements in AI-based bioinformatics technologies have led to a better understanding of prion biology and strain diversity. The future holds promise for utilising cutting-edge treatment techniques, such as CRISPR and gene therapy, for targeted interventions, as well as combining AI with multimodal data to enhance diagnostic capabilities. There is optimism that the burden of prion disorders can be reduced, and the treatment of neurodegenerative illnesses can be improved through the integration of molecular research, novel treatments, and AI technology.

Alzheimer's disease (AD) is a typical neurodegenerative illness, and it is a main cause of dementia, affecting millions of older populations throughout the world. Although the exact causes of AD are still not clear, the disorder is known to be considered by the accumulation of amyloid plaques and tau tangles in the neuronal cells. Currently, available drugs such as cholinesterase inhibitors and NMDA antagonists can help manage symptoms but don’t address the underlying causes of the disease. New experimental treatments targeting amyloid and tau proteins show promise but are still in clinical trials. Recently, β-Amyloid has gained attention as an emerging target to develop new medications as it is strongly involved in the pathophysiology of AD. β-Amyloidpathies are directly or indirectly linked with multiple pathways, including GSK3β, insulin resistance, NMDA dysfunction, AMP-activated kinase, cholesterol mechanism, mitochondrial dysfunction, neuroinflammation, and SIRT1. However, several β-Amyloid targeting therapies employing various mechanisms have shown partial success in clinical trials, possibly due to a lack of understanding of the molecular link of this peptide with other pathways. Therefore, this paper has discussed the β-Amyloid molecular mechanisms involved in pathophysiological pathways to manage neuronal disorders and intracellular signal transduction effectively.

The zebrafish (Danio rerio) is widely utilised as a live vertebrate model in research on neurological development and nervous system diseases. This species exhibits various distinctive attributes that render it well-suited for investigating neurological disorders such as Parkinson’s disease (PD). Zebrafish and humans have a genetic similarity of around 70%, and approximately 84% of the genes associated with human diseases have zebrafish equivalents. The genetic similarities and presence of neurotransmitters like dopamine allow scientists to study PD genes and proteins. Zebrafish are often challenged with neurotoxins to induce Parkinsonian symptoms, allowing researchers to evaluate attendant biochemical pathways. Zebrafish can also repair damaged organs, increasing their potential value in PD research. Because of their regenerative capacity and genetic resemblance to humans, these species can be used to study dopamine neurodegeneration and prospective PD treatments. In addition to PD, zebrafish are helpful models for studying Huntington's disease, Alzheimer's disease, epilepsy, depression, schizophrenia, and anxiety disorders. This article emphasizes significant findings of relevance to PD using the zebrafish model, describing its challenges and benefits. The investigation of key genes, protein pathways, and neurotoxins provides the opportunity to facilitate understanding of the role of dopamine neurotransmitters in PD and

expedite the development of potentially promising therapeutic strategies.

Alzheimer's disease (AD) is a devastating neurological disorder that affects humans and is a major contributor to dementia. It is characterized by cognitive dysfunction, impairing an individual's ability to perform daily tasks. In AD, nerve cells in areas of the brain related to cognitive function are damaged. Despite extensive research, there is currently no specific therapeutic or diagnostic approach for this fatal disease. However, scientists worldwide have developed effective techniques for diagnosing and managing this challenging disorder. Among the various methods used to diagnose AD are feedback from blood relatives and observations of changes in an individual's behavioral and cognitive abilities. Biomarkers, such as amyloid beta and measures of neurodegeneration, aid in the early detection of Alzheimer's disease (AD) through cerebrospinal fluid (CSF) samples and brain imaging techniques like Magnetic Resonance Imaging (MRI). Advanced medical imaging technologies, including X-ray, CT, MRI, ultrasound, mammography, and PET, provide valuable insights into human anatomy and function. MRI, in particular, is non-invasive and useful for scanning both the structural and functional aspects of the brain. Additionally, Machine Learning (ML) and deep learning (DL) technologies, especially Convolutional Neural Networks (CNNs), have demonstrated high accuracy in diagnosing AD by detecting brain changes. However, these technologies are intended to support, rather than replace, clinical assessments by medical professionals.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Emerging evidence highlights the significant role of glial cells, particularly astrocytes and microglia, in the pathophysiology of ASD. Glial cells are crucial for maintaining homeostasis, modulating synaptic function, and responding to neural injury. Dysregulation of glial cell functions, including altered cytokine production, impaired synaptic pruning, and disrupted neuroinflammatory responses, has been implicated in ASD. Molecular mechanisms underlying these disruptions involve aberrant signaling pathways, such as the mTOR pathway, and epigenetic modifications, leading to altered gene expression profiles in glial cells. Moreover, microglial activation and reactive astrocytosis contribute to an inflammatory environment that exacerbates neural circuit abnormalities. Understanding these molecular mechanisms opens avenues for therapeutic interventions. Current therapeutic approaches targeting glial cell dysfunction include anti-inflammatory agents, modulators of synaptic function, and cell-based therapies. Minocycline and ibudilast have shown potential for modulating microglial activity and reducing neuroinflammation. Additionally, advancements in gene editing and stem cell therapy hold promise for restoring normal glial function. This abstract underscores the importance of glial cells in ASD. It highlights the need for further research to elucidate the complex interactions between glial dysfunction and ASD pathogenesis, aiming to develop targeted therapies that can ameliorate the clinical manifestations of ASD.