Initiation and propagation of molecular cascades in human brain aging: Insight from the canine model to promote successful aging

1. Normal aging is thought to proceed through two stages: initiation and pr opagation. Each of these phases is associated with different neuroanatomica l events, vulnerabilities to injury and responsiveness to interventions. 2. The role of beta-amyloid (A beta) in neuron dysfunction in the initiatio n stage may be mediated through alterations in signal transduction pathways involving cyclic AMP response element binding protein (CREB). CREB phospho rylation is associated with the expression of brain derived neurotrophic fa ctor (BDNF), which promotes neuron health and survival. In primary neuronal cultures, AP decreases the phosphorylation of CREB, which results in up to a 31% decrease in BDNF levels. 3. In vivo studies also support a role for AP in neuron dysfunction since s oluble ap levels correlate with the loss of synapses in brains of non-demen ted humans with high pathology. 4. The authors hypothesize that interventions during the initiation stage, when neuron dysfunction, but not overt pathology, is present, have the most promise to promote successful aging. The dog can serve as a useful model f or interventions during the initiation stage since dogs develop neuropathol ogy that closely resembles that observed in high pathology human brains.