Cortical Synaptogenesis and Behavioural Consequences in CNS Lesioned Animals Receiving Neurotrophic Factor Therapy

Abstract

The ultimate goal in neurodegenerative disease therapy is the preservation of neuronal somata and their synaptic connections. In this regard, there is overwhelming experimental evidence that these objectives can be met with the application of neurotrophic factors in diverse lesion models leading to anterograde or retrograde neuronal degeneration. The issue of whether neurotrophic factor administration can re-establish or regenerate new synaptic contacts has been recently reviewed in the context of future neurotrophic factor based therapies (Cuello and Thoenen, 1995). However, much has yet to be learned on the limits and possible undesirable effects of this approach. Thus, in recent attempts to apply purified mouse nerve growth factor (NGF) in Alzheimer’s disease (AD) the treatment had to be interrupted due to weight loss and cefalalgias (Sieger et al., 1993). Indeed, excessive NGF offering provokes ectopic synaptic formation of peptide-containing terminals within the white matter of transgenic mice overexpressing chick NGF, produced by oligodendrocytes during early post-natal stages (Ma et al., 1995). Will trophic therapy, therefore, be undesirable in AD? I would like to propose that neurotrophic factors (NTFs) have a defined opportunity in AD therapy provided that some basic conditions are met. These should be, firstly, early treatment, at a stage when there is sufficient regenerative capacity left in the diseased brain to respond to NTFs, an approach which is currently hampered by the lack of presymptomatic biological diagnosis. Secondly, much has yet to be learned about the specificity, interactions and dosage of NTFs capable of provoking synaptogenesis in the cerebral cortex accompanied by desirable behavioural effects. Thirdly, the field anxiously awaits a suitable animal model for AD where these (and other) propositions can be properly and exhaustively investigated.