New Studies Outline Immune Cell and Protein Interactions Crucial for Defense Against Neurodegenerative and Inflammation-Based Diseases
Two new publications from Cedars-Sinai neuroscientists are helping to advance scientific understanding of the complex molecular and cellular processes involved in听鈥攁nd the body鈥檚 innate immune mechanisms for fighting against the condition, as well as other diseases.
听published in听Frontiers in Immunology听offers broader insight into the protein networks that allow immune cells to respond to harmful substances. This discovery could lead to treatments that leverage the body鈥檚 natural healing processes.
鈥淭his study demonstrates enormous potential for exploiting the natural immune process to better fight disease,鈥� said听, a professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the听study. 鈥淲hite blood cells鈥攚hich we studied here in the context of Alzheimer鈥檚 disease鈥攁re one of the first lines of defense against a variety of foreign and internal threats and are key for regulating tissue repair and maintenance.鈥�
Altan Rentsendorj, PhD
The study demonstrates the significance of osteopontin (OPN), a protein expressed by macrophages, a type of white blood cell that surrounds and destroys harmful organisms and clears cell debris and the buildup of abnormal proteins. Investigators, in collaboration with the听听at Cedars-Sinai, concluded that OPN deficiency disrupts the balance of proteins in macrophages, eventually causing them to die.
鈥淢acrophages clear toxic proteins, reduce inflammation, and help regenerate, rejuvenate, and encourage newly formed connections in the brain,鈥� said Koronyo-Hamaoui.
The study builds on two previous studies from the Koronyo-Hamaoui Llab鈥攑ublished in听听and听鈥�detailing the critical role played by bone-marrow derived macrophages and OPN expressed in macrophages in clearing Alzheimer鈥檚 disease-related amyloid-beta peptides and supporting central nervous system repair and regeneration.
Ron Danziger, MD
鈥淥ur work supports further study into gene editing or immunotherapies that could have multifaceted impact,鈥� said Altan Rentsendorj, PhD, a senior research associate in the听听and first author of the study.
Investigators studied macrophages in laboratory mice. They compared normal cells, diseased cells treated with an FDA-approved multiple sclerosis treatment that caused them to overexpress OPN, and cells without the ability to produce OPN.
They found that diseased macrophages treated with the multiple sclerosis medication more effectively cleared amyloid-beta proteins and increased their anti-inflammatory activity. However, in cells without the ability to produce OPN, treatment with the multiple sclerosis medication did not restore normal protein expression.
Investigators also discovered that the presence of OPN is necessary to produce two other crucial anti-inflammatory molecules. Dysfunction of the first, ubiquitin C-terminal hydrolase L1, has been implicated in neurodegenerative diseases such as Alzheimer鈥檚. The second, heme oxygenase 1, plays a critical role in preventing vascular inflammation.
鈥淲e were surprised to find that other neuroprotective proteins are dependent on OPN,鈥� Rentsendorj said. 鈥淭his work shows that OPN is critical for the machinery of rejuvenation in these innate immune cells.鈥�
The Koronyo-Hamaoui Lab also recently published听听in听Frontiers in Physiology听synthesizing knowledge about angiotensin converting enzyme (ACE) and its role in Alzheimer鈥檚 disease. ACE, expressed by immune cells, degrades amyloid-beta and improves immune response.
The review outlines findings from 1975 onward, including numerous studies from the Koronyo-Hamaoui Lab in collaboration with the听听at Cedars-Sinai.
Significant among these are a 2020 paper published in听,听which demonstrated that overexpression of ACE enhances the ability of white blood cells called monocytes to rid the body of toxic forms of amyloid-beta oligomers and fibrils, and a 2014 paper published in听. The review also notes that an analysis of human genome sequencing found people with a genetic variant that leads to lower expression of ACE in their blood had higher risk for Alzheimer's disease.
鈥淭his review builds a strong case for targeting monocytes and ACE in Alzheimer's disease,鈥� said neurology fellow Ron Danziger, MD, first author of the review paper. 鈥淚n extensive studies by the Koronyo-Hamaoui and Bernstein labs, we have consistently found an amazing effect of ACE on the characteristics of macrophages in the context of Alzheimer鈥檚 disease.鈥�
Taken together, the new papers support the need for further research into therapies that might leverage immune function in blood or bone marrow cells to fight neurodegenerative disease.
Keith L. Black, MD
鈥淲e need a much more effective treatment to address many aspects of Alzheimer鈥檚 disease,鈥� said听, chair of the Department of Neurosurgery, the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, and co-author of both studies. 鈥淕enetically manipulating monocytes to enhance ACE or OPN, which would target more than plaque clearance, could be a very promising technique.鈥�
Funding: The study appearing in听Frontiers in Immunology听was funded by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG056478, R01AG055865, AG056478-04S1 and R01AG075998) and the Tom Gordon, Haim Saban and Wilstein foundations.
The study appearing in听Frontiers in Physiology听was supported by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG055865, R01AG056478, R01AG075998 and R01AG042195); a BrightFocus Foundation Award; The Coins for Alzheimer鈥檚 Research Trust (CART) Fund; the Cedars-Sinai Jona Goldrich Center for Alzheimer鈥檚 and Memory Disorders; the Saban, Gordon, Marciano and Wilstein private foundations; and the National Center for Advancing Translational Sciences (CTSI grant UL1TR000124).
