Mechanisms underlying age-related cognitive decline and sensitivity to brain-derived neurotrophic factor.

摘要

Age-related changes in hippocampal-dependent memory are well documented. Despite the role of entorhinal cortex (EC) in hippocampal circuitry, examination of EC within the context of aging has been minimal. Further, there is strong evidence that neurotrophic factors, including brain-derived neurotrophic factor (BDNF), can modulate synaptic plasticity. Thus, we have examined hypotheses of both cell loss and dysfunction in EC with aging and determined whether or not BDNF delivery to EC improves hippocampal-dependent memory in aged rats.; Potential cell loss was examined by stereologically counting neurons in aged monkeys and behaviorally characterized aged rats. Contrary to long-held dogma, but in agreement with more recent stereological reports, significant neuronal loss was not associated with aging in EC. Further, age-related decreases in hippocampal neurogenesis were examined in the rat dentate gyrus. Behavioral performance was not significantly correlated with level of neurogenesis in aged rats. Thus, it appears that changes in cell number do not underlie dysfunction of hippocampal circuitry in brain aging, but rather, that degenerative events in neuronal metabolism and projections are more likely candidates.; Thus, we have also studied aspects of neuronal function with aging in EC. We found that levels of the calcium-binding protein calbindin were altered in relation to cognitive status with aging and correlated with spatial learning ability. While BDNF levels were not altered with aging, analysis of BDNF-TrkB signaling pathways revealed a selective decline in the activation of TrkB/Erk signaling, a pathway known to be important in neuronal survival and differentiation, in aged-impaired but not aged-unimpaired animals. To characterize sensitivity of age-related cognitive decline to BDNF infusion, we infused BDNF bilaterally into the entorhinal cortex of aged-impaired rats and assessed hippocampal-dependent memory using the Morris water maze. We found that BDNF significantly improved spatial learning and memory and that the aforementioned deficit in TrkB/Erk signaling was reversed by BDNF infusion. Collectively, findings of this dissertation indicate that neuronal dysfunction, rather than frank cell loss, accompanies cognitive decline with aging. Further, this work suggests a novel therapeutic potential of neuronal growth factors to reverse aspects of such age-related neuronal dysfunction and ameliorate the associated cognitive decline.