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Updated: Aug 5, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
New insights on microglial lysosomal acidification: A therapeutic target of neurodegenerative diseases
Ravindran Jaganathan1, Srilakshmi Vijayakumar2, Yinchi Chen3
1Preclinical Department, Faculty of Medicine, Royal College of Medicine Perak, Universiti Kuala Lumpur, Perak, Malaysia.
Background:
Microglia, the resident immune cells of the central nervous system (CNS), maintain brain homeostasis and respond to pathological insults. Microglial dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Impaired lysosomal function, particularly defective lysosomal acidification, leads to the accumulation of undegraded material, thereby promoting neuroinflammation and neuronal damage.
Purpose:
This review examines the mechanisms governing lysosomal acidification in microglia and evaluates its potential as both a therapeutic target and a prognostic biomarker in neurodegenerative diseases.
Methods:
The literature on microglial lysosomal acidification, lysosomal pH regulation, autophagy, and neurodegeneration was searched in PubMed, Scopus, and Web of Science. Relevant mechanistic, preclinical, and translational studies were critically appraised and synthesized.
Results:
Lysosomal acidification is increasingly recognized as a key regulator of microglial function and homeostasis. Defective acidification, driven by dysregulation of the vacuolar H+-ATPase (V-ATPase) proton pump, TFEB/TFE3 signaling pathways, and lysosomal ion channels such as TRPML1 and TMEM175, impairs autophagic flux and substrate degradation, facilitating the accumulation of neurotoxic aggregates including amyloid-β and α-synuclein. Emerging evidence suggests that the degree of microglial lysosomal acidification may serve as a prognostic biomarker for disease progression and therapeutic response. Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models.
Conclusion:
Restoration of microglial lysosomal acidification represents a promising therapeutic strategy for neurodegenerative diseases. A deeper understanding of the molecular mechanisms regulating lysosomal acidification in microglia may facilitate the identification of novel biomarkers and therapeutic targets, ultimately contributing to the development of innovative interventions for neurodegenerative disorders.
Insights
Restoring lysosomal acidification in microglia is a promising therapy for neurodegenerative diseases. This process is crucial for maintaining brain health and could serve as a biomarker for disease progression.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are central nervous system immune cells vital for brain homeostasis.
- Microglial dysfunction and impaired lysosomal acidification contribute to neurodegenerative diseases like Alzheimer's and Parkinson's.
- Defective lysosomal acidification leads to toxic material buildup, promoting neuroinflammation and neuronal damage.
Purpose of the Study:
- To review mechanisms of microglial lysosomal acidification.
- To evaluate lysosomal acidification as a therapeutic target and prognostic biomarker in neurodegenerative diseases.
Main Methods:
- Literature search of PubMed, Scopus, and Web of Science.
- Inclusion of mechanistic, preclinical, and translational studies.
- Critical appraisal and synthesis of relevant research.
Main Results:
- Lysosomal acidification regulates microglial function; its defect impairs autophagy and causes neurotoxic aggregate accumulation.
- Dysregulation of V-ATPase, TFEB/TFE3 pathways, and ion channels (TRPML1, TMEM175) underlies defective acidification.
- Microglial lysosomal acidification levels may predict disease progression and treatment response.
Conclusions:
- Restoring microglial lysosomal acidification is a potential therapeutic strategy for neurodegenerative disorders.
- Understanding regulatory mechanisms can identify new biomarkers and therapeutic targets.
- This research may lead to innovative interventions for neurodegenerative diseases.
