Pro-neurotrophin receptor sortilin in neurodegenerative processes and Alzheimer's disease

Sortilin is a member of the VPS10P domain receptor gene family, a novel class of sorting and signalling receptors in neurons. This gene family also includes SORLA/LR11, the neuronal sorting receptor for APP. Sortilin has been shown to constitute an essential component of the receptor complex that transmits pro-neurotrophin-dependent death signals in neurons. In previous studies, sortilin-dependent pro-neurotrophin signalling has been implicated in regulation of neuronal viability during normal development and aging. Also, sortilin activity has been shown to control neuronal death and survival in spinal cord injury. Remarkably, up-regulation of pro-neurotrophins has been observed under conditions of neurodegeneration. These findings led us to hypothesize that sortilin signaling may not only control neuronal viability during acute but also during chronic distress of the nervous system as in Alzheimer's disease (AD). Here, we have used mice with targeted sortilin gene disruption to address the consequences of impaired sortilin activity for APP processing, structural and functional integrity of the brain, as well as AD pathology in vivo. Mice lacking sortilin were characterized by accelerated APP processing and a concomitant change in several neuronal signaling pathways including ERK1/2, PKBa, JNK, and PKA. Alterations in neuronal signaling did not affect viability of neurons as determined by stereological counting. However, loss of sortilin activity was accompanied by distinct changes in cognitive performance of affected mice. Ongoing experiments aim at further elucidating possible roles for sortilin in the progression and outcome of neurodegenerative processes in AD.