Role of Neurotrophins in the Maintenance of BFCNs Structure and Function

Neurotrophin (NT) family members in mammals include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, and NT4/5 (see Sofroniew, Howe, & Mobley, 2001). NTs exert their action via two different receptors, p75NTR and the tyrosine kinase receptors of the Trk family. p75NTR, the common NT receptor, is a member of the tumor necrosis factor family; it is a single-span glycosylated transmembrane receptor that binds all NTs with nanomolar affinity. In addition to p75NTR, each NT binds to specific Trk family members, again with nanomolar affinity. There are three members of this family; TrkA binds NGF, TrkB binds BDNF and NT4, and TrkC binds NT3. NGF signaling through TrkA elicits the classical actions ascribed: survival of immature neurons, and increased differentiation and maintenance of mature neurons (Loeb et al., 1991; Sofroniew et al.). NGF binding causes TrkA dimer-ization and autophosphorylation of tyrosine residues that serve as binding sites for adaptor proteins that mediate downstream signaling events including those mediated by Ras, Rap1, PI3K, and PLC-y (Sofroniew et al., 2001).

NGF serves as a target-derived neurotrophic factor for BFCNs; it is synthesized and released by cortical and hippocampal neurons (Korsching, Auburger, Heumann, Scott, & Thoenen, 1985). This is followed by binding to its receptors before internalization and retrograde transport of NGF-NGF receptor complexes to BFCN cell bodies (Howe & Mobley, 2005; Sofroniew et al., 2001). In many ways, the response of BFCNs to NGF mirrors those of NGF-responsive populations in the peripheral nervous system, i.e., nociceptive dorsal root ganglion (DRG) neurons and sympathetic neurons (Sofroniew et al., 2001). During brain development, NGF promotes the survival and differentiation of cholinergic neurons of the basal forebrain (Chen & Gage, 1995; Li et al., 1995; Mobley, Rutkowski, Tennekoon, Buchanan, & Johnston 1985). However, in adults, it appears that NGF acts to maintain the mature function and structure of BFCNs without being required for survival (see Sofroniew et al., 2001; Ruberti et al., 2000). Mice heterozygous for Ngf (i.e., Ngf+/-) during the life span showed in adulthood a significant reduction in (1) the number and size of cholinergic immunoreactive (ChAT-Ir) neurons in the MSN, (2) ChAT activity levels in hippocampus, and (3) the density of AChE-positive fibers in the hippocampus. In the Morris water maze, Ngf+/-mice took significantly longer to find a hidden platform (Chen et al., 1997).

In contrast, depriving adult BFCNs of the MSN of their hippocampal target, the principal source of NGF, resulted in a decrease in NGF protein levels and atrophy of BFCNs without cell loss (Cooper, Skepper, Berzaghi, Lindholm, & Sofroniew, 1996; Ruberti et al., 2000; Sofroniew et al., 1993). A similar pattern for the age dependency of NGF actions is evident in vitro. Svendsen, Kew, Staley, and Sofroniew (1994) studied NGF in rat septal cultures. NGF withdrawal in 14-day-old cultures was accompanied by significant loss of cholinergic cells, as marked by immunostaining for ChAT, AChE or p75NTR. In contrast, when NGF was withdrawn from mature septal cultures (35-day old), the response was characterized principally by cellular shrinkage (Svendsen et al., 1994). Thus, it appears that a classical target-driven relationship exists for NGF and BFCNs.

All NTs are able to upregulate ChAT and AChE levels in cultured rat BFCNs, but NT3 effects are limited to cultures obtained during embryonic life. Comparing the NTs for their effect on the number of ChAT-positive neurons in postnatal septal cultures, NGF showed the most robust effects (Nonomura, Nishio, Lindsay, & Hatanaka, 1995).

In light of the degeneration of BFCNs in AD, the important roles that NGF signaling plays, especially in the maintenance of BFCN structure and function, have motivated a careful look at the possibility that disruption of NGF signaling could play a role in pathogenesis and that NGF treatment could be used to prevent or delay degenerative changes. Indeed, mice in which NGF signaling is disrupted recapitulate important features of the changes in BFCNs detected in AD (Ruberti et al., 2000).

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