The Department of Defense–funded study; entitled: "Inhibition of Soluble TNF Mitigates Traumatic Brain Injury as a Risk Factor for the Development of Amyloidogenic Proteins and Functional Deficits in 3xTg-AD Mice"; found that a single brain injury raised two proteins central to Alzheimer’s biology, the inflammatory cytokine tumor necrosis factor (TNF) and the neurotoxic form of amyloid beta (Aβ42), and that treatment with the Company’s lead neuroinflammation candidate, XPro1595, prevented the injury-induced rise in amyloid pathology.

TBI is among the strongest environmental risk factors for later dementia, yet the biology linking the two has been unclear. These findings implicate soluble TNF, the disease-driving form of the cytokine, as a key link, and show that selectively neutralizing it can interrupt the inflammatory cascade before amyloid pathology takes hold.

TBI raised brain levels of TNF, its receptor TNFR1, and Aβ42, and produced deficits in learning and memory and pain. In comparison, animals treated with XPro1595 showed reduced TNF, no injury-induced rise in Aβ42, improved learning and memory within one week of injury, and reduced pain compared to vehicle-treated injured animals.

"For a long time we’ve known that a traumatic brain injury raises the risk of Alzheimer’s disease without really understanding why. These data point to soluble TNF as a key part of that link: neutralizing it early kept the injury from triggering the rise in amyloid-related proteins and prevented the memory and pain deficits that usually follow, reinforcing how central neuroinflammation is to the onset of Alzheimer’s pathology," said study author (and funding Principal Investigator) Dr. Kirsty Dixon, Associate Professor of Surgery at Virginia Commonwealth University.  "While we’ll continue to study the relationship between inflammation and Alzheimer’s, these findings suggest there may be a role in the treatment continuum for selectively targeting soluble TNF, both for younger people who suffer a head injury and for Alzheimer’s patients, who are especially prone to falls and other injuries."

Male 3xTg-AD mice, a well-characterized Alzheimer’s model, received either a single moderate TBI or a sham procedure and were treated with either XPro1595 or vehicle. Researchers measured brain cytokines, inflammatory markers, and AD-related proteins such as Aβ42, and assessed the animals for deficits in cognition and mechanical hypersensitivity.

"These independent findings reinforce the thesis behind our approach: selectively neutralizing soluble TNF to interrupt the neuroinflammation that drives Alzheimer’s pathology. Seeing that mechanism prevent both amyloid accumulation and functional decline in a model of injury-accelerated Alzheimer’s adds to a growing body of evidence supporting soluble TNF as a target across neurodegenerative disease," said David Moss, Chief Executive Officer of INmune Bio.