CNS & Neurological Disorders - Drug Targets - Volume 25, Issue 1, 2026

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, 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.

Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.