Long-lasting cognitive injury in rats with apparent full gross neurological recovery after short-term cardiac arrest.

OBJECTIVE: The long-term behavioral effects of mild global ischemia have not been well described. We used short (5 min) asphyxic-cardiac arrest that resulted in no apparent gross neurological deficits to study the long-term effects of mild hypoxic ischemia on the neurobehavioral status of rats. METHODS: Fifteen adult, male Wistar rats were studied. One group was given asphyxic-cardiac arrest (CA) for 5 min (n=10) and the other group had Sham procedure (n=5). Neurobehavioral testing was performed before and 2 weeks after CA. The neurobehavioral evaluations were: neurological deficit score (NDS), Y Maze, open field, pre-pulse inhibition (PPI) of acoustic startle reflex (ASR), wire hanging, and inclined screen. RESULTS: At 24h post-CA, all of the rats regained normal neurological function as measured by NDS, an integral score for consciousness, brainstem reflexes, sensorimotor function and simple behavioral reflex tests. However, 1 week after CA, the rats exhibited significant activity reductions in the open field and in spontaneous alternation in the Y maze. The CA rats also showed a significant decrease in startle reaction amplitude and startle inhibition in the PPI tests. Two weeks after CA, the changes in motor activity and deficits in PPI remained significant, but the spontaneous alternation recovered. The muscle strength test of wire hanging and inclined screen tests did not exhibit significant change. CONCLUSION: We present a rodent model of mild CA that, despite apparent full recovery of global neurological function at 24h post-resuscitation, exhibited long-term cognitive injury lasting for at least 2 weeks after CA. This model may help understand better the injury associated with CA and develop management strategies for mild brain injury.

BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.

A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta (Abeta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to Abeta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Abeta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1DeltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. Moreover, Abeta deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1(-/-) mice are prevented by coexpressing APPswe;PS1DeltaE9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate Abeta amyloidosis in AD.