The Effect of Chronic Gamma-Secretase Modulation on the Prevention of Traumatic Brain Injury-Provoked and Alzheimer’s Disease-Relevant Biochemical, Pathological and Behavioral Alterations


The clinical manifestations of traumatic brain injury include impairments in sensory, motor, psychiatric and cognitive function. At the molecular level, traumatic brain injury gives rise to accumulation of a number of proteins in the axons of neurons. Axons are the long projections of neurons that conduct electrical impulses known as action potentials. Several of the proteins that compose these aggregates in the axon include those that play a role in Alzheimer’s disease: amyloid precursor protein, amyloid beta-42, hyperphosphorylated tau and neurofilament light chain. Axonal injury is thought to occur immediately after traumatic brain injury. Interventions targeting mechanisms that generate amyloid beta-42 may ameliorate the axonal damage and spread of amyloid elicited by traumatic brain injury.

The implications for this intervention would be the reduction of the risk of developing Alzheimer’s disease or related dementias. Gamma-secretase is one of the two enzymes responsible for amyloid beta-42 production. Compounds that modulate this enzyme may be able to curtail the production of toxic amyloid beta-42. Using medicinal chemistry, this research will optimize a series of novel gamma-secretase modulators with the hope of developing a preventive treatment for traumatic brain injury-induced neurodegeneration.

Funding to Date



Drug Discovery, Translational Research


Brian P. Head, Ph.D.

Steven Wagner, Ph.D.