Neuropathogenesis-on-chips for neurodegenerative diseases: This review explores the use of microfluidic chips and organoids-on-chips as advanced models for studying neurodegenerative diseases (NDs). These models offer a more accurate representation of human pathophysiology compared to traditional animal models, enabling the study of complex pathogenic features such as neuronal loss, gliosis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular damage in diseases like Alzheimer's, Parkinson's, ALS, and Huntington's. The integration of microfluidic chips, stem cells, and biotechnological devices provides valuable insights for biomedical research and the development of diagnostic and therapeutic solutions for NDs. As life expectancy increases, the incidence of NDs is rising due to an aging population. Despite extensive research, the development of disease-modifying treatments remains challenging. Current animal models differ significantly from humans in immune systems and brain cell composition, limiting their effectiveness. Advanced in vitro models, such as organoids, are needed to better replicate human pathogenesis and improve drug development. Stem cell-based 3D culture platforms have enabled the creation of organoids for disease modeling and drug screening. However, current organoid models have limitations, including insufficient neuronal functionality and lack of vascular and immunological components. Microfluidic organs or organoids-on-chips provide unique opportunities for studying disease-specific environments, biochemical cues, and cell interactions, offering a more accurate representation of in vivo conditions. Recent studies have shown that microfluidic chips can enhance organoid development by controlling expansion, integrating vascular beds, and allowing co-culturing with systemic microglia. These models are being used in drug screening and basic life science studies, with potential applications in understanding neuropathogenesis and developing targeted therapies. Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles, with pathogenesis involving amyloid-β and tau protein dysfunction, neuroinflammation, and mitochondrial dysfunction. Tau hyperphosphorylation is closely linked to cognitive decline, and the spread of toxic tau shows prion-like behavior. Aβ and tau pathology are interconnected, with Aβ accumulation inducing tau aggregation and vice versa. Parkinson's disease is marked by the accumulation of misfolded α-synuclein, leading to Lewy body formation. Misfolded α-synuclein aggregates can self-propagate, contributing to neuronal toxicity. Protein degradation pathways, such as the ubiquitin-proteasome system and autophagy-lysosomal pathway, are disrupted in PD, leading to the accumulation of misfolded proteins. Mitochondrial dysfunction is a key factor in PD pathogenesis, with α-synuclein inhibiting mitochondrial pathways and causing oxidative stress. Environmental factors, such as neurotoxic chemicals and heavy metals, also contribute to ND pathogenesis. The development of advanced in vitro models, including microfluidic chips and organoids-on-chips, is crucialNeuropathogenesis-on-chips for neurodegenerative diseases: This review explores the use of microfluidic chips and organoids-on-chips as advanced models for studying neurodegenerative diseases (NDs). These models offer a more accurate representation of human pathophysiology compared to traditional animal models, enabling the study of complex pathogenic features such as neuronal loss, gliosis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular damage in diseases like Alzheimer's, Parkinson's, ALS, and Huntington's. The integration of microfluidic chips, stem cells, and biotechnological devices provides valuable insights for biomedical research and the development of diagnostic and therapeutic solutions for NDs. As life expectancy increases, the incidence of NDs is rising due to an aging population. Despite extensive research, the development of disease-modifying treatments remains challenging. Current animal models differ significantly from humans in immune systems and brain cell composition, limiting their effectiveness. Advanced in vitro models, such as organoids, are needed to better replicate human pathogenesis and improve drug development. Stem cell-based 3D culture platforms have enabled the creation of organoids for disease modeling and drug screening. However, current organoid models have limitations, including insufficient neuronal functionality and lack of vascular and immunological components. Microfluidic organs or organoids-on-chips provide unique opportunities for studying disease-specific environments, biochemical cues, and cell interactions, offering a more accurate representation of in vivo conditions. Recent studies have shown that microfluidic chips can enhance organoid development by controlling expansion, integrating vascular beds, and allowing co-culturing with systemic microglia. These models are being used in drug screening and basic life science studies, with potential applications in understanding neuropathogenesis and developing targeted therapies. Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles, with pathogenesis involving amyloid-β and tau protein dysfunction, neuroinflammation, and mitochondrial dysfunction. Tau hyperphosphorylation is closely linked to cognitive decline, and the spread of toxic tau shows prion-like behavior. Aβ and tau pathology are interconnected, with Aβ accumulation inducing tau aggregation and vice versa. Parkinson's disease is marked by the accumulation of misfolded α-synuclein, leading to Lewy body formation. Misfolded α-synuclein aggregates can self-propagate, contributing to neuronal toxicity. Protein degradation pathways, such as the ubiquitin-proteasome system and autophagy-lysosomal pathway, are disrupted in PD, leading to the accumulation of misfolded proteins. Mitochondrial dysfunction is a key factor in PD pathogenesis, with α-synuclein inhibiting mitochondrial pathways and causing oxidative stress. Environmental factors, such as neurotoxic chemicals and heavy metals, also contribute to ND pathogenesis. The development of advanced in vitro models, including microfluidic chips and organoids-on-chips, is crucial