Abstract
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)P2, 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.
Highlights
Fifty million people worldwide currently present with neurodegenerative conditions, with 60–70% of these suffering from Alzheimer’s disease (AD) (World Alzheimer Report, 2015)
This study demonstrated how homozygous deficiency of TLR2 or 3 or heterozygous deficiency of TLR4 was able to extend lifespan in an HD mouse model (Griffioen et al, 2018)
The microglial function is severely impaired in a variety of ways within neurodegenerative conditions, with these cells typically showing heightened activation states from early stages of disease development, often before symptom onset
Summary
Fifty million people worldwide currently present with neurodegenerative conditions, with 60–70% of these suffering from Alzheimer’s disease (AD) (World Alzheimer Report, 2015). AD, first characterized by Alois Alzheimer in 1907 (Alzheimer et al, 1995), presents with widespread brain atrophy, amyloid plaques (large extracellular deposits of amyloid-beta (Aβ) protein aggregates), neurofibrillary tangles (consisting of phosphorylated Tau), neuronal and synapse loss, and dystrophic neurites (Lane et al, 2018) These pathologies result in memory loss, language difficulties, executive dysfunction, psychiatric symptoms, and behavioral disturbances, along with general difficulties managing activities of daily living (Burns and Iliffe, 2009). C9orf knock-out mice, while showing no motor-neuron degeneration, show altered immune responses in microglia and macrophages, highlighting the importance of these myeloid cells in ALS pathogenesis (O’Rourke et al, 2016) Another ALS risk gene, TBK1, is involved in the production of inflammatory cytokines (Ahmad et al, 2016). More research must be undertaken to fully elucidate the role of microglia in ALS pathology
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