Immune-regulating brain cells known as microglia are known to play a role in the progression of Alzheimer’s disease (AD). Investigators at Brigham and Women’s Hospital studying the genetics of microglia have now found that a reduction the activity of a gene called INPP5D in these cells results in neuroinflammation, and increases the risk for AD. The results could have important implications for the design of microglia-centered therapeutics for Alzheimer’s disease and related disorders.

“We know that microglia play important roles in the healthy and diseased brain, but, in many cases the molecular mechanisms underlying this relationship are poorly understood,” said Tracy Young-Pearse, PhD, from the department of neurology at Brigham and Women’s Hospital. “If we’re able to identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics.”

Young-Pearse is corresponding author of the team’s published paper in Nature Communications, which is titled, “INPP5D regulates inflammasome activation in human microglia.” In their paper, the team concluded, “These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.”

Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease, and there is an increasing focus on understanding the role of microglia in neurodegenerative disorders including late-onset Alzheimer’s disease (LOAD),” the authors wrote. LOAD is defined by the accumulation of amyloid beta-rich plaques, and neurofibrillary tangles. But while it is important to monitor neuroinflammation in people with neurodegenerative diseases—the earlier neuroinflammation is identified, the earlier it can be treated—it can be difficult to detect, especially in the early stages of AD.

Microglia are clearly involved in the process of neuroinflammation, but there are many unanswered questions regarding the molecular pathways involved. “Microglia play a variety of key roles during disease progression through synaptic engulfment, cytokine release, and phagocytosis of amyloid beta,” the investigators pointed out.  However, commonly, “the molecular mechanisms underlying the consequences of perturbation of AD-associated genes in microglia are poorly understood.”

Interrogating the connections between genetic risk factors for AD and inflammatory cascades will be important for identifying new therapeutic strategies for AD, the investigators also pointed out. “One such genetic risk factor highly expressed in myeloid cells is INPP5D.” For their reported study, the team used a variety of experimental approaches to probe the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. “The inflammasome is a multimeric complex involved in innate immune signaling that is induced in response to inflammatory insults,” the team explained.

As part of the study, they compared human brain tissue from patients with AD and from control individuals. They found lower levels of INPP5D in the tissues of patients with AD and when INPP5D was reduced, it activated inflammation. “… in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD,” they wrote.

In parallel, the investigators used living human brain cells derived from stem cells to study the intricate molecular interactions within microglia that mediate inflammatory processes with a reduction of INPP5D. These studies identified specific proteins that could be inhibited to block inflammasome activation in microglia. “Through unbiased RNA and proteomic profiling and a series of pharmacological manipulations, we demonstrate that reduction of INPP5D activity in microglia induces changes in immune signaling and, more specifically, the activation of the NLRP3 inflammasome,” they stated.

Although the team’s work represents the most comprehensive analysis of INPP5D in the AD brain, it remains to be determined whether INPP5D should be targeted with therapeutics. The team noted that their findings suggest INPP5D activity in AD brains is complex and future studies are needed to understand if INPP5D can be targeted to prevent cognitive decline in patients with AD. “A key question surrounds whether INPP5D is a feasible target for therapeutic development in AD,” they wrote. “Selective agonists and antagonists have been developed for INPP5D but the biology of INPP5D in the AD brain is complex and it is not immediately apparent whether INPP5D activity should be enhanced or inhibited for therapeutic benefit.”

Young-Pearse added, “Our results highlight an exciting promise for INPP5D, but some questions still remain. Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD.”

The authors further noted in their discussion, “Our data suggest that understanding the interplay of signaling mechanisms between INPP5D activity and inflammasome regulation could be key to unraveling aspects of the early stages of microglial involvement in AD … Using a multi-omic approach,we provide rich sets of data that, taken together, suggest that a reduction in function of INPP5D in microglia results in inflammasome activation in the AD brain and that reduced INPP5D activity can have transcriptional consequences on neurons.” These datasets, they suggested, provide important clues to unraveling the signaling mechanisms that connect INPP5D to the inflammasome.

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