Pluripotent Stem (iPS) Cells Shed Light on How a Patient With a History of Concussion May Progress to a Neurodegenerative Condition

Pluripotent Stem (iPS) Cells Shed Light on How a Patient With a History of Concussion May Progress to a Neurodegenerative Condition

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Pluripotent stem (iPS) cells have allowed neuroscientists to investigate the impact of mild traumatic brain injury (TBI) in ways never thought possible. Now neuroscience is attempting to understand and predict who, how, and when a patient with a history of concussion will progress to a neurodegenerative condition, including Alzheimer’s disease (AD). Brain injury has always presented challenges in predicting long-term outcomes. With most human pathology, tissue samples can disclose abnormalities. However, in living humans (in vivo), we don’t extract brain tissue unless absolutely necessary.

Traumatic brain injury is a disorder on a spectrum ranging from mild to severe. It is estimated that 80% of TBI falls into the “mild” category that would include concussion. The more severe end of the TBI spectrum is generally identifiable with standard clinical imaging like CT scan or MRI. Currently, there is an ongoing review of the “mild” classification of TBI because, for a large cohort of patients, the only thing mild is the label. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Board on Health Sciences Policy; Committee on Accelerating Progress in Traumatic Brain Injury Research and Care. Traumatic Brain Injury: A Roadmap for Accelerating Progress. Matney C, Bowman K, Berwick D, editors. Washington (DC): National Academies Press (US); 2022 Feb 1.

It is now undisputed that most patients who have suffered a concussion that proves to be chronic likely suffer from microscopic injury to white matter fibers in the brain. The injury has been referred to as axonal injury, diffuse axonal injury, and now simply traumatic axonal injury. Currently, there are limited techniques available to assess the damage to neural structures in vivo, leaving it to clinicians to correlate findings of probable white matter damage with other clinical evidence.

A recent paper reports on the use of human induced pluripotent stem cells (hiPSCs) as proxies for neurons that are subjected to mild stretching to simulate the forces of concussion. It was reported that the mild deformation of the cells triggered the production of Amyloid Precursor Protein (APP) in a process known as amyloidogenic APP cleavage. This was the beginning of a degenerative but non-lethal secondary process that led to an abnormal accumulation of APP and beta Amyloid Precursor (Aβ). It is suspected that when the response disrupts the transport of APP, it limits the neuro-protective potential of APP. The process described is considered to be a factor in the early onset of Alzheimer’s disease. Almenar-Queralt A, Dos Santos Chaves R, Kwon EJ, Shah SB. Heads Up! Interlinked Amyloidogenic and Axonal Transport Pathways in Concussion-Induced Neurodegeneration. Neurosci Insights. 2022 Oct 17;17:26331055221129641.