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 propagation. Each of these phases is associated with different neuroanatomical events, vulnerabilities to injury and responsiveness to interventions. 2. The role of β-amyloid (Aβ) in neuron dysfunction in the initiation stage may be mediated through alterations in signal transduction pathways involving cyclic AMP response element binding protein (CREB). CREB phosphorylation is associated with the expression of brain derived neurotrophic factor (BDNF), which promotes neuron health and survival. In primary neuronal cultures, Aβ 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 Aβ in neuron dysfunction since soluble Aβ levels correlate with the loss of synapses in brains of non-demented 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 for interventions during the initiation stage since dogs develop neuropathology that closely resembles that observed in high pathology human brains