Clinical manifestations of TBI are complex and are associated with sensory, motor, psychiatric and cognitive impairments stemming from a multifaceted series of biochemical, morphological and structural alterations resulting in axonal accumulation and aggregation of a number of proteins and peptides such as APP, Aβ42, hyperphosphorylated tau (tau-P) and neurofilament light chain (NFL); additional proteins increase in plasma such as S100B (cerebrovascular damage), GFAP (astroglial injury), UCH-L1 (neuronal damage) and NFL. Morphologically, diffuse axonal injury (DAI) occurs immediately after TBI. Increases in intra-axonal APP, a well-established marker for DAI following TBI used to identify DAI in forensic medicine. In addition, TBI-induced elevations in Aβ peptides, especially Aβ42, chronically has been shown to potentiate Aβ deposition in transgenic AD mouse models. Therefore, interventions targeting mechanisms generating Aβ42 may serve to ameliorate axonal damage as well as amyloidosis elicited by TBI and reduce the risk of developing AD or related dementias. γ-secretase is one of the two enzymes responsible for Aβ42 production, therefore, compounds that modulate (rather than inhibit) this pivotal enzyme may be able to safely curtail Aβ42. We successfully developed a series of novel GSMs through iterative rounds of medicinal chemistry optimization. UCSD/MGH-776890 and UCSD/MGH-779690 potently (IC50 = 4.1 nM and 5.3 nM, respectively) lower Aβ42 in vitro and exhibit excellent drug-like properties (in vitro ADMET and in vivo pharmacokinetic parameters) in multiple species. Repeat-dose efficacy studies in rodents (5-10 mg/kg/day) dramatically lower Aβ42 levels in brain, CSF and plasma while displaying no toxicity at a dose of >50 mg/kg/day. Pharmacodynamics studies show that a single oral dose (5-10 mg/kg) suppresses Aβ42 levels in brain and plasma for up to 24 hrs. These strong proof-of-concept findings support the further preclinical evaluation of UCSD/MGH-776890 and UCSD/MGH-779690 as potential preventative treatments for TBI-induced chronic neurodegeneration.
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.