Hypoxic-ischemic (HI) encephalopathy (HIE) is the most frequent cause of acute acquired brain injury in infants and imparts a life-long morbidity that is not well described. Long term clinical and behavioral follow-up into adulthood is lacking, but recent MRI studies of former preterm infants with neonatal brain injury reveals degeneration in the basal forebrain and marked symptoms of executive dysfunction similar to adult neurodegenerative diseases. The acute mechanisms of injury in both HIE in infants and several other causes of brain injury in children and teens involve excitotoxicity, oxidative injury, and neurotrophin abnormalities that can cause plasma membrane alterations, mitochondrial, endoplasmic reticulum (ER), chromatin, and nuclear dysfunction that instigate cell death. This is followed by astrocyte and microglial activation with prominent neuroinflammation. The persistence of these mechanisms following the injury is not well described but ER dysfunction, gliosis and ongoing neuroinflammation last well beyond the subacute phase in preclinical models of neonatal HI. ER dysfunction, gliosis and ongoing neuroinflammation are well recognized as primary etiologic mechanisms in adult neurodegenerative diseases including Alzheimer's Disease (AD). We have identified ultrastructural abnormalities in the mouse basal forebrain nucleus basalis of Meynert caused by neonatal HI that manifest in adulthood. Moreover, there are potential global abnormalities in tau phosphorylation in brains of these mice reminiscent of AD. Blood serum immunoassays reveal abnormalities in A? proteins as well as prolonged elevation of inflammatory biomarkers in these mice. Because neonatal HIE and early life traumatic brain injury share multiple similar early and subacute pathogenic mechanisms and early life traumatic brain injury unquestionably results in early AD and similar diseases, we question whether neonatal HI results in long term neuropathology similar to adult onset neurodegenerative diseases and whether neonatal HI in a genetically susceptible model, causes premature onset of manifestations of adult neurodegeneration. We will explore these question with the following Aims.
Aim 1 : Determine whether neonatal HI causes age-related neuropathology consistent with adult forms of neurodegeneration.
Aim 2 : Determine whether neonatal HI causes neurobehavioural manifestations consistent with adult forms of neurodegeneration.
Because hypoxic-ischemic (HI) brain injury at birth and early life brain trauma share many similar features and because early life traumatic brain injury unquestionably results in early Alzheimer's Disease, we are investigating whether neonatal HI results in brain changes similar to Alzheimer's disease and whether neonatal HI speeds up the appearance of Alzheimer's disease in genetically susceptible mice.
