Soluble factors released from astrocytes modulate the insulin-like growth factor receptor (IGF1-R) expression in cortical neurons during in vitro senescence.

Late-onset Alzheimer’s disease (AD) is the World’s most prevalent form of dementia and one of most common age-releated diseases. The abnormal accumulation of amyloid β-peptides (Aβ) is considered the main pathogenetic event responsible for the loss of synapses and neurons and the consequent cognitive decline. Although aging represents the single most important risk factor for Alzheimer’s disease, the molecular events that connect normal aging to AD are unkown. Recently it has been shown that during normal aging, Aβ generation in the brain is induced by a switch from the TrkA to p75NTR neurotrophin receptor, that leads to the activation of neutral sphingomyelinase and liberation of the lipid second messenger ceramide, which in turn is responsible for the molecular stabilization of BACE1 and the production of Aβ. An increased expression of insulin-like growth factor receptor (IGF1-R) during aging is responsible for the switch of the two neurotrophin receptors (Costantini et al. EMBO J. 2006), thus representing an interesting target for prevention. However, the molecular mechanism(s) that regulate the IGF1-R expression in brain during aging are not known. Here, by using long-term neuronal cultures as a model of aging (Lesuisse et al J. Neurobiol. 2002), we report data showing that soluble factors released from glial cells modulate IGF1-R expression in neurons during senescence. In fact: i) IGF1-R expression does not increase in neuronal cell cultures where the proliferation of glial cells was prevented by cytosine β-D-arabinofuranoside hydrochloride (Ara-C) treatment; ii) the addition of conditioned medium from a 24-days-old neuronal culture (high percentage of glial cells and high expression of IGF1R) to a 3-days-old neuronal culture (low percentage of glial cells and low expression of IGF1R) induces an increase of IGF1-R expression; iii) co-culturing Ara-C-treated neurons with primary astrocytes in the presence of a transwell that physically separates the two cell populations, but allows the passage of soluble factors, increases the expression of IGF1-R in neurons. Studies are now under investigation in order to identify the glial-derived soluble factors responsible for the modulation of IGF1-R expression.