Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration
Open accessAbstract
Microglia are increasingly recognized as vital players in the pathology of a variety of neurodegenerative conditions including Alzheimer’s (AD) and Parkinson’s (PD) disease. While microglia have a protective role in the brain, their dysfunction can lead to neuroinflammation and contributes to disease progression. Also, a growing body of literature highlights the seven phosphoinositides, or PIPs, as key players in the regulation of microglial-mediated neuroinflammation. These small signaling lipids are phosphorylated derivates of phosphatidylinositol, are enriched in the brain, and have well-established roles in both homeostasis and disease.Disrupted PIP levels and signaling has been detected in a variety of dementias. Moreover, many known AD disease modifiers identified via genetic studies are expressed in microglia and are involved in phospholipid metabolism. One of these, the enzyme PLCγ2 that hydrolyzes the PIP species PI(4,5)P 2 , displays altered expression in AD and PD and is currently being investigated as a potential therapeutic target.Perhaps unsurprisingly, neurodegenerative conditions exhibiting PIP dyshomeostasis also tend to show alterations in aspects of microglial function regulated by these lipids. In particular, phosphoinositides regulate the activities of proteins and enzymes required for endocytosis, toll-like receptor signaling, purinergic signaling, chemotaxis, and migration, all of which are affected in a variety of neurodegenerative conditions. These functions are crucial to allow microglia to adequately survey the brain and respond appropriately to invading pathogens and other abnormalities, including misfolded proteins. AD and PD therapies are being developed to target many of the above pathways, and although not yet investigated, simultaneous PIP manipulation might enhance the beneficial effects observed. Currently, only limited therapeutics are available for dementia, and although these show some benefits for symptom severity and progression, they are far from curative. Given the importance of microglia and PIPs in dementia development, this review summarizes current research and asks whether we can exploit this information to design more targeted, or perhaps combined, dementia therapeutics. More work is needed to fully characterize the pathways discussed in this review, but given the strength of the current literature, insights in this area could be invaluable for the future of neurodegenerative disease research.
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PI(3,4,5)P3 can be converted back to PI(4,5)P2 by PTEN or converted into PI(3,4)P2 by SHIP1, which negatively regulates PI3K/Akt signaling.
“PI(3,4,5)P3 can be converted back to PI(4,5)P2 by the protein phosphatase and tensin homology (PTEN) or converted into PI(3,4)P2 by SHIP1, which negatively regulates PI3K/Akt signaling (Fig. 2) [89–92].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [90]
The Chemotaxis and Migration section (page not available) says PTEN converts PI(3,4,5)P3 back to PI(4,5)P2. The Endocytosis section (page not available) says SHIP promotes conversion of PI(3,4,5)P3 to PI(3,4)P2, but does not identify it as SHIP1 or state that this conversion negatively regulates PI3K/Akt signaling. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSHIP1 is a phosphatase involved in phosphoinositide signaling.
“SHIP1 is a phosphatase involved in phosphoinositide signaling.”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [90]
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Targeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities
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Microglial activation in the pathogenesis of Huntington's disease
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P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology
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Mutant huntingtin impairs immune cell migration in Huntington disease
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Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
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“, 2019), appears to protect via increased PLCγ2 activity (Magno et al., 2019).”
BackgroundToll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies
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A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P2
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SH3PXD2A LEVELS IN ALZHEIMER’S DISEASE: AN EXPLORATORY STUDY OF A POTENTIAL SYNAPTIC BLOOD BIOMARKER
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- Authors
- Ernest James Phillips, T., & Maguire, E.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- Maguire, Emily
- ORCID
- Maguire, Emily
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2021-03-26
- Volume
- 15
- Pages
- 652593-652593
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC8032904
- OpenAlex
- W3140288526
- Cited by
- 33
- References
- 376
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 2 · 2021: 3
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Society
- Cardiff University
- UK Dementia Research Institute
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- phosphoinositides, microglia, neuroinflammation, neurodegeneration, Alzheimer's disease, Parkinson's disease, PLCγ2, phosphatidylinositol 4,5-bisphosphate, phospholipid metabolism, endocytosis, Toll-like receptor signaling, purinergic signaling, chemotaxis, microglial migration, microglial dysfunction
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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