The role of neurotrophins in brain aging: a perspective in honor of Regino Perez-Polo.

During brain aging and progression of Alzheimer's disease, the levels of Abeta and proinflammatory cytokines accumulate very early in the pathogenic process prior to any major degenerative changes. Accumulation of these molecules may impair with signal transduction pathways critical for neuronal health. Neurotrophin signaling is a critical mechanism involved in synaptic plasticity, learning and memory and neuronal health. We have recently shown that exposure to low levels of Abeta impairs BDNF trkB signal transduction, suppressing the Ras/ERK, and the PI3-K/Akt pathways but not the PLCgamma pathway. As a result, downstream regulation of gene expression and neuronal viability are impaired. Recently, we have found that at least three agents--Abeta, TNFalpha, Il-1beta--suppress TrkB signaling and act via a common and novel mechanism. These factors all regulate the docking proteins (e.g., IRS and Shc) that link the activated Trk receptor to downstream effectors. While this is a novel mechanism underlying regulation of Trk signaling, such a mechanism has been identified for the insulin/IGF-1 receptor in the presence of proinflammatory cytokines and is one of the mechanisms for insulin/IGF-resistance, which is a key risk factor for type II diabetes (1). We suggest that accumulation of AB and proinflammatory cytokines during aging generates in the brain a "neurotrophin resistance" state that places the brain at risk for cognitive decline and dementia.