The concept of neurotrophic factors

The concept of neurotrophic factors can be traced back to the discoveries of a phenomenon and a molecule, i.e., ontogenetic neuron death and the first neurotrophic factor, nerve growth factor (NGF; Hamburger and Oppenheim 1982; Cowan 2001; Aloe 2004). The neurotrophic hypothesis postulates that developing post-mitotic neurons in the peripheral nervous system are generated in excess and compete during well-defined time windows for survival-promoting molecules, which are synthesized in limited amounts in the neuronal target tissue. These survival-ensuring molecules bind to specific receptors on the neuronal membrane, are internalized into axon terminals and transported retrogradely to the cell body, where they regulate translational and transcriptional events resulting in survival and differentiation. As a consequence of the limited availability of the factors in the peripheral targets, a defined number of neurons undergoes apoptotic death (Oppenheim 1991; Lewin and Barde 1996; Perez-Polo 2006; Pong Ng et al. 2006). However, competition for neurotrophic factors as a survival-determining mechanism of developing neurons does not seem to account for neurons of the central nervous system (CNS) in general. For example, the developmental death of cortical interneurons, which originate far from the cerebral cortex, has been shown to be an intrinsically determined process that occurs without interference from the target (Southwell et al. 2012).

Discoveries made during the past two decades have not only added many new facets to the classic neurotrophic factor hypothesis but also revealed an initially unexpected complexity in the number of neurotrophically acting molecules, their receptors and diversity of functions. As shown in Fig. 1, anterograde trophic signaling and local actions of neurotrophic factors have been added to the classic retrograde pathway for mediating trophic effects (Korsching 1993). Glial cells have been acknowledged as important sources and targets of neurotrophic factors and mediators of indirect neurotrophic effects (von Bohlen und Halbach and Unsicker 2013). Similarly, neurons have been recognized as a site of origin of neurotrophic factors and different neurotrophic factors have been shown to exert overlapping, yet distinct patterns of activity and divergent functions when acting in different contexts (Korsching 1993). The actions of neurotrophic factors on synaptic efficacy and the regulation of their expression by electrical activity have indicated that they play crucial roles in regulating neuronal connectivity (Lewin and Barde 1996). Perhaps most strikingly, endogenous NGF has been shown to act as a death-promoting factor when signaling through the non-tyrosine kinase receptor p75, a member of the tumor necrosis factor (TNF) receptor and Fas family (Frade et al. 1996; Lu et al. 2005). In a similar vein, the neurotrophin receptors TrkA (tropomyosin-related kinase A) and TrkC but not TrkB, have been revealed to cause neuronal death, thus explaining why developing sympathetic and sensory neurons become trophic-factor-dependent for survival (Nikoletopoulou et al. 2010). In summary, the broad repertoire of functions that neurotrophic factors possess and their contextualities in cooperation with other factors have to be taken into account when considering their application in therapies of neurodegenerative disease.

Fig. 1
figure 1

Sources and directions of signaling of neurotrophic molecules. A The “classic” retrograde signaling pathway involves a target cell (here: a neuron) as the source of the molecule, the release of the molecule, its binding to an axon terminal and its retrograde transport to the neuronal perikaryon. B Glial cells, including Schwann cells, astrocytes, oligodendrocytes and microglia, can synthesize and release neurotrophic factors. C Autocrine mode of neurotrophic factor stimulation. D Anterograde signaling of neurotrophic factors. Modified from Korsching (1993)

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The spectrum of neurotrophic factors

Neurotrophins and their receptors

Neurotrophins, the classic neurotrophic factor family, comprise NGF, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and NT-4 (also known as NT-5), NT-6 and NT-7 (Huang and Reichardt 2001). They probably arose through successive duplications of the genome of an ancestral chordate (Hallbrock 1999). The NT-6 and NT-7 genes are only found in fish and do not seem to have mammalian orthologs. The structures of neurotrophins have been solved and several features of their structures, e.g., the cystine knot, are present in other growth factors (McDonald et al. 1991; McDonald and Chao 1995). A receptor now named p75 was the first identified neurotrophin receptor. It was initially believed to be a low-affinity receptor for NGF but was later shown to bind all neurotrophins with similar affinities (Rodriguez-Tebar et al. 1991). The cytoplasmic domain of p75 contains a “death” domain shared with other members of the TNF receptor family, thereby eliciting death when activated separate from the trk neurotrophin receptors. The Trk family of neurotrophin receptors comprises TrkA, which is preferentially activated by NGF, TrkB, the key receptor for BDNF and NT-4 and TrkC, preferentially used for NT-3 signaling (Reichardt 2006). Phosphorylation of the tyrosines within the Trk kinase domain and docking of adaptor proteins are indispensible for triggering several intracellular signaling pathways, including the Ras-mitogen-activated protein kinase, phosphatidyl inositol 3 (PI3)-kinase and phospholipase C-gamma pathways (Fig. 2; cf. review by Pong Ng et al. 2006).

Fig. 2
figure 2

Representation of neurotrophin (NT) signaling (Trk tropomyosin-related kinase, PI3K phosphatidyl inositol 3-kinase, Shc Src homology 2 domain containing, Gab2 GRB2-associated binding protein 2, Shp2 tyrosine phosphatase, Akt protein kinase B, Ras rat sarcoma protein, Raf rapidly accelerated fibrosarcoma protein, Rap Ras-related protein, MEK mitogen-activated protein kinase kinase, ERK extracellular-signal-regulated kinase, PLC phospholipase C)

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BDNF is the most abundant neurotrophin in the brain (Barde et al. 1982) and seems to exist as pro-BDNF and “mature” BDNF. “Mature” BDNF is the predominant form and is crucially involved in physiological processes in the intact adult brain, including morphological and functional synaptic plasticity, long-term potentiation, learning and memory. Because of its wide distribution in the CNS, it is the neurotrophin with the largest therapeutic potential in CNS disorders, such as Alzheimer’s, Parkinson’s and Huntinton’s disease, stroke, depression and metabolic disorders (reviewed by Nagahara and Tuszynski 2011).

BDNF and NGF in the treatment of neurodegenerative diseases

Stroke is the most common neurological disorder affecting mostly the cerebral cortex. The grafting of a BDNF-expressing cell line or the intravenous systemic injection of BDNF has been shown to reduce neuron death after middle cerebral artery occlusion and photothrombotic ischemia, respectively (Ferrer et al. 2001; Müller et al. 2008). However, major obstacles to treatment, as for other widespread brain lesions, are the delivery of sufficiently high concentrations of stable BDNF to the lesioned areas over long periods of time and the putative adverse effects. Drugs, e.g., antidepressants and AMPA (2-amino-3-[3-hydroxy-5-methyl-isoxazol-4-yl]propanoic acid) receptor agonists, which increase the endogenous expression of BDNF, might turn out to be useful in BDNF therapies. Moreover, small molecule BDNF mimetics that bind to TrkB and trigger downstream signaling have been shown to be useful therapeutic drugs in initial studies (Massa et al. 2010; Jang et al. 2010; Monteggia 2011). Whether gene therapy as a tool to deliver BDNF can become an established method and a reliable therapeutic alternative in widespread CNS lesion paradigms remains to be investigated.

Treatment of Alzheimer’s disease with BDNF basically implies similar challenges concerning delivery. Both BDNF gene delivery and protein administration to the entorhinal cortex, a key region in the initiation of Alzheimer’s disease (Braak and Braak 1991; Kordower et al. 2001), have been successfully used in rodent and primate models of the disease. Therapeutic improvements include those to memory, cell survival, cell body size and extracellular-signal-regulated kinase (ERK) signaling and normalized gene expression but no change in amyloid plaques (Nagahara et al. 2009; Nagahara and Tuszynski 2011). Significant improvement in the rate of cognitive decline has been reported in six patients suffering from Alzheimer’s disease following implantation of autologous fibroblasts genetically modified to express human NGF into the forebrain (Tuszynski et al. 2005). No adverse effects have been observed in this study. A link between beneficial neural stem cell transplantation and BDNF secretion by the grafted hippocampal neural stem cells in a transgenic model of Alzheimer’s disease has been reported by Blurton-Jones et al. (2009). Grafts rescue spatial learning and memory deficits, effects that are mimicked by recombinant BDNF and abolished when BDNF is depleted from the neural stem cells. Together, these results are sufficiently encouraging for the further exploration of the therapeutic potential of BDNF and NGF and the collection of additional sets of data to support their efficacy and safety profile with the goal of initiating clinical trials.

Parkinson’s disease is a chronic progressive neurodegenerative disease that afflicts more than five million people worldwide. Degeneration of midbrain dopaminergic neurons in the substantia nigra and subsequent depletion of dopamine in the striatum, together with the presence of Lewy bodies containing alpha-synuclein in the surviving substantia nigra dopaminergic neurons, are pathological hallmarks of the disease. Current understanding of the “idiopathic” disease is incomplete, despite considerable advances in understanding the pathogenesis of familial forms of Parkinson’s disease. Although both genetic and lesion-based animal models are available, models that recapitulate the chronic disease in detail are still lacking (however, see Decressac et al. 2011, 2012a, b). Replacement of dopamine is the currently available symptomatic therapy. Although physiological roles of neurotrophic factors in dopaminergic neurons of the aging midbrain are not comprehensively understood, several members of the neurotrophin family and other growth factor families have been tested in animal models and administered in patients (Aron and Klein 2011). BDNF is one of several growth factors that promote the survival of both cultured and in-vivo-lesioned midbrain dopaminergic neurons (Hyman et al. 1991). Substantial evidence suggests that BDNF infused or released from genetically engineered fibroblasts protects dopaminergic neurons in the substantia nigra from toxic insults (Levivier et al. 1995; Frim et al. 1994; Tsukahara et al. 1995). Whether inhibitors of the type B monoamine oxidase (MAO), namely rasagiline, selegiline and (−)deprenyl, prevent dopaminergic neuron loss by increasing the expression of BDNF and putatively of other neurotrophic factors is the subject of controversy (Maruyama and Naoi 2012; Weinreb et al. 2007). As shown by Flannery et al. (2010), selegiline increases BDNF content in the striatum by 32% but this change does not reach statistical significance.

Details of the application of BDNF in other neurodegenerative diseases such as Huntingtons’s disease, amyotrophic lateral sclerosis (ALS) and spinal cord injury, can be found in Nagahara and Tuszynski (2011).

Neurotrophins in ocular disease

In the normal adult retina, the NGF receptor TrkA is expressed in retinal ganglion cells (RGCs), whereas p75 is found in Müller glia (Bai et al. 2010). Injury of the retina causes the upregulation of TrkA, p75 and NGF. However, neither endogenous NGF nor exogenously administered NGF can ultimately protect degenerating RGCs. The selective activation of TrkA with a mutant NGF or the prevention of endogenous NGF and pro-NGF from binding to p75 protect RGCs in glaucoma or following optic nerve transection. Selective activation of p75 causes RGC death in normal eyes and accelerates RGC death after injury. The activation of p75 during glaucoma-driven retinal degeneration has been suggested to enhance the synthesis and release of neurotoxic molecules, e.g., TNF-α (Bai et al. 2010). Although the complete details of the retinal NGF and NGF receptor networks are currently not understood, increasing evidence indicates that a fragile balance of ligand and receptors needs to be achieved for the protection of RGCs (Lebrun-Julien et al. 2009; Sposato et al. 2008; Coassin et al. 2008). Somewhat surprisingly, NGF administered to the cornea has been shown to protect RGC in models of glaucoma and diabetic retinopathy (Colafrancesco et al. 2011; for a review of NGF in ocular diseases, see Lambiase et al. 2011). Whereas such results are certainly spectacular, they should be rigorously tested not only with regard to the transport of iodinated NGF by using the full spectrum of available molecular and cell biological methodologies.

RGCs also express TrkB (Fischer 2012) and so do several other neuronal cell types in the retina. A vast literature documents that BDNF delays RGC death after axotomy and in several other lesion models. Many modes of application have been used, including stem-cell-based delivery (Harper et al. 2011; S.H. Park et al. 2010; H.Y. Park et al. 2012), recombinant adeno-associated viral vectors (Rodger et al. 2012; Ren et al. 2012; Isenmann et al. 1998), adenovirus-infected Müller cells (Di Polo et al. 1998) and combinatorial treatment with other factors, e.g., the leucine-rich repeat protein LINGO-1 (Fu et al. 2009). TrkB-mediated protection from light has also been documented following the use of N-acetylserotonin (Shen et al. 2012). BDNF gene delivery has also been shown to protect the structure and function of light-damaged photoreceptors (Gauthier et al. 2005). Expression of TrkB by RGC also indicates that NT-4 is a candidate for protecting against retina injury (Peinado-Ramon et al. 1996; Watanabe et al. 1997). However, we need to take into account that, when administered for therapeutic purposes, BDNF/TrkB signaling not only stimulates the growth of axonal branches of RGC (Sawai et al. 1996) but can also profoundly refine RGC dendritic arborization and connectivities (Liu et al. 2007). Finally, two more caveats should be pointed out: first, the manipulation of growth factor expression almost inevitably affects the expression of other growth factors, as exemplified by the heterozygote BDNF+/− retina with its significantly increased levels of glial-cell-line-derived neurotrophic factor (GDNF; Wilson et al. 2007); second, BDNF is anterogradely transported by RGC to the superior colliculus and lateral geniculate (Caleo et al. 2000; Bartheld 1998) and therefore, its overexpression in the eye will probably have an impact on these structures and further distal parts of the visual pathway.

NT-3 has been less extensively studied in the retina and RGCs, which express the cognate receptor trkC (Fischer 2012). During development, NT-3 and trkC expression is widespread in retinal neuroepithelial progenitor cells (Das et al. 2000). Later, in a mouse strain carrying the reporter gene LacZ, NT-3 is transiently restricted to a small subset of cells in the inner nuclear and ganglion cell layers, whereas in the adult mouse eye, NT-3 expression is confined to the corneal epithelium (Bennet et al. 1999). In a model of open angle glaucoma, levels of retinal NT-3, in contrast to trkC and NGF, remain unchanged (Rudzinski et al. 2004). Peinado-Ramon et al. (1996) have found that the intraocular administration of NT-3 does not modify the survival of RGCs after injury. Together, these data do not suggest that NT-3 is a promising candidate for the treatment of RGC injury.

As a general note, for the screening of molecules with a potential neuroprotective capacity for RGCs, retinal explant models have been developed and can be used for efficient medium-throughput screening (Bull et al. 2011).

Neuroregulatory cytokines—the ciliary neurotrophic factor (“neurokine”) family

Ciliary neurotrophic factor (CNTF) was the first purified and cloned non-neurotrophin neurotrophic factor (Stöckli et al. 1989; for a review, see Halvorsen and Knaur 2006). It was the founding member of a gene family that shares a gp130 receptor subunit with other neuroregulatory cytokines, including leukemia inhibitory factor (LIF), interleukin-6 (IL-6), cardiotrophin-1 and −2 (CT-1, CT-2), oncostatin-M and neuropoietin (Fig. 3). Their biological actions are diverse and include prominent roles in the hematopoietic system and in the nervous system. Their signaling is mediated through the Janus tyrosine kinase and activator of transcription (JAK/STAT) pathway. Whereas none of the family members appears to be essential by itself, the deletion of each of the individual receptor subunits is not compatible with life. CNTF and LIF gene knockouts result in modest motoneuron defects, which are potentiated in CNTF/LIF-double and CNTF/LIF/CT-1 triple knockouts (cf. Holtmann et al. 2005).

Fig. 3
figure 3

Members of the ciliary neurotrophic factor (CNTF) family and their cognate receptors (LIF leukemia inhibitory factor, IL interleukin, CLC cardiotrophin-like cytokine, NP neuropoietin, CT cardiotrophin, OSM oncostatin-M, R receptor). Modified from Halvorsen and Knaur (2006)

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Neuroregulatory cytokines in the treatment of neurodegenerative diseases

CNTF and related cytokines play many roles in neurodegenerative diseases and trauma. They can be induced or can promote the injury response including the survival of injured cells. Hippocampal and entorhinal cortex lesions are accompanied by the increased expression of CNTF and CNTF-α-receptor by astrocytes (C.K. Park et al. 2000; Lee et al. 1997). Several animal models of motor neuron disease, including pmn and Wobler mice, have revealed responses to exogenous and endogenous neuroregulatory cytokines (Sendtner et al. 1992, 1997; Mitsumoto et al. 1994). Hopes that CNTF might be effective in ALS have not been substantiated (ALS study group 1996). However, encouraging data have been reported from experiments in an Alzheimer’s disease mouse model with recombinant cells secreting CNTF encapsulated in alginate polymers (Garcia et al. 2010).

CNTF and related molecules in ocular disease

The neurokine family and its receptors are well represented in the retina. CNTF is expressed in pigment epithelium and Müller glia (Finn and Nishi 1996; Walsh et al. 2001). RGCs express gp130, CNTF receptor alpha and LIF receptor β (Fischer 2012), suggesting that they are responsive to the corresponding ligands. In culture, CNTF and LIF delay rod cell development (Kirsch et al. 1998) and CNTF redirects rods to bipolar, amacrine and Müller glia cells (Ezzedine et al. 1997). The effect of intraocularly administered CNTF on the viability of RGCs is controversial (Cui et al. 1999; Barnstable and Tombran-Tink 2006). Despite a lack of effect on RGC survival following optic nerve transection and insertion of a sciatic nerve graft, as reported in this study, the intravitreal application of CNTF substantially enhances regeneration (Cui et al. 1999). CNTF also remarkably prevents RGC loss in a rat model of posterior ischemic optic neuropathy (Wang et al. 2012). In combination with lens injury or intravitreal application of zymosan, RGCs switch into an active regenerative state. The promoting effect on survival and axon regeneration is mediated by CNTF (Leibinger et al. 2009). The axon-growth-promoting effect of lens crystallins is also generated by enhancing the production of CNTF (Thanos et al. 2012). In a search for mechanisms underlying the axon-regenerative capacity of CNTF, the investigation of a possible involvement of STAT3, which has been shown to act locally in axons of motoneurons to modify the tubulin cytoskeleton (Selvaraj et al. 2012), will be important. Interestingly, exogenous CNTF also induces endogenous CNTF expression in glial cells (Müller et al. 2009). In agreement with the established effects of CNTF on photoreceptors (see above), intravitreal injections of a human CNTF analog (Axokine, Regeneron) significantly delays photoreceptor loss in a feline model of rod-cone dystrophy (Chong et al. 1999). Several recent reports corroborate the notion of CNTF being a potent trophic molecule for photoreceptors. End-stage photoreceptor degeneration has been successfully treated with CNTF in many animal models and in humans (Wen et al. 2012a, b). Application by encapsulated cell technology might be preferred following the documentation of delivery over a period of 2 years and a favorable pharmacokinetic profile (Kauper et al. 2012). With a perspective towards using CNTF therapeutically, we should however note that long-term gene therapy has been reported to cause aberrant dendritic RGC morphology and stratification (Rodger et al. 2012). With regard to the efficacy of other members of the neurokine family on RGCs, IL-6, which is upregulated in injured RGCs in experimental glaucoma, potently stimulates axon regeneration of RGCs in culture (Caraci et al. 2012).

The fibroblast growth factor family

The fibroblast growth factor (FGF) family comprises 23 members each of which signals via four tyrosine kinase receptors (FGFR1-FGFR4) that exist in many splice variants (for a review, see Unsicker et al. 2006). Since the first reports of the neurotrophic functions of FGF-2 in the late 1980s, numerous other functions have been discovered for FGFs in the nervous system in which more than a dozen FGF family members are expressed. FGF-2 is primarily synthesized by astrocytes, whereas other FGF members (FGF-1, -5, -8, -9, -10, -15, -18) are predominantly synthesized by neurons. Similar to the postulated functions of other growth factor families, the neural functions of FGFs are often extrapolations from pharmacological experiments and applications of exogenous FGFs. Although a loss of cortical neurons in FGF-2-deficient mice might suggest a role of this FGF as a neurotrophic factor (Dono et al. 1998), the activities of FGF-2 in relation to the generation and migration of neurons place a strong caveat on such an interpretation. This also applies to another widely popularized function of FGF-2, i.e., its assumed role in adult neurogenesis (Werner et al. 2011).

FGFs in neurodegenerative disease

Mitogenic and differentiative effects on astrocytes and neurotrophic survival-promoting effects are the earliest described neural functions of FGFs, most notably of FGF-2 (cf. Bieger and Unsicker 1996; Unsicker et al. 1987). Several distinct mechanisms seem to account for the neurotrophic functions of FGF-2, including interference with neurotransmitter receptors and combinatorial actions with other growth factors (Unsicker et al. 2006). The in vivo capacity of FGFs to protect lesioned neurons and to orchestrate responses to lesions has been widely documented (Unsicker et al. 2006). Probably the most intensely studied neurons protected by FGFs are midbrain dopaminergic neurons in the substantia nigra (Otto and Unsicker 1990, 1993a, b; von Bohlen und Halbach and Unsicker 2013). Within the abundance of reports documenting enhanced survival of impaired neurons as a prominent function of FGFs, the loss of FGF-2 accounting for the prolonged survival and milder impairment of motor function in an SOD1 ALS mouse model has come as a surprise (Thau et al. 2012), underscoring the complexity of the growth factor networks involved in neurodegenerative and regenerative events. Several neurodegenerative diseases, as exemplified by Huntington’s disease, seem to benefit from the neuroprotective and neuroproliferative capacities of FGF-2 (Jin et al. 2005). Even the most complex psychiatric disorders, e.g., major depression, seem to result from the imbalanced expression of FGFs and apparently respond to endogenous and exogenous FGF (Riva et al. 2005; Jarosik et al. 2011; Turner et al. 2012).

FGFs in ocular disease

FGF has well-documented protective effects on the viability of photoreceptors and RGCs (Cui et al. 1999; Joly et al. 2007). The capacity of FGF-1 and FGF-2 to protect RGCs following transection of the optic nerve was the first neural lesion paradigm in which the neurotrophic potential of these FGFs was documented in vivo (Sievers et al. 1987). Mechanistically, FGF-2 has been shown to increase Bcl-2 and to decrease Bax in RGCs by activating the ERK pathway (Rios-Munoz et al. 2005). In addition to FGF-1 and FGF-2, other members of the FGF family have established their potential to rescue photoreceptors and RGCs in models of retinal degeneration. For example, FGF-5 and FGF-18 rescue photoreceptors from apoptosis in a recombinant adeno-associated virus-mediated paradigm of retinitis pigmentosa (Green et al. 2001). Similarly, FGF-19 has been shown to protect adult mammalian photoreceptors (Siffroi-Fernandez et al. 2008). When considering FGFs for therapy, small molecules, e.g., Enreptin, which activate both FGF receptors and the FGF co-receptor NCAM (neural cell adhesion molecule), might have distinct advantages (Ernevoldsen et al. 2012). However, when administering FGF for therapeutic purposes, the mitogenic and angiogenic properties of FGF always constitute obstacles that can probably only be overcome by developing FGF agonists lacking these side effects.

The transforming growth factor family

The transforming growth factor-β family (TGF-β) comprises more than 30 secreted proteins that regulate numerous developmental processes, control tissue homeostasis and mediate repair (Böttner et al. 2000; De Robertis and Kuroda 2004; Derynck and Zhang 2003;Derynck and Akhurst 2007; Krieglstein et al. 2011). A major function of TGF-β related to this Special Issue is the control of neuron survival (Unsicker and Krieglstein 2002; Krieglstein 2006). However, since both neurons and glial cells express TGF-βs and the congnate receptors, functions of TGF-βs are extremely diverse and difficult to extrapolate (Krieglstein 2006). More recently, their involvement in synaptic functions have begun to come to light (Krieglstein et al. 2011). TGF-β members play crucial roles in diseases including neurodegenerative disorders (Flanders et al. 1998); as typical, contextually acting, growth factors, they do so by diverse cross-talk with other growth factors (Ikushima and Miyazono 2012; Massagué 2012). TGF-βs are almost ubiquitously expressed, with all three isoforms TGF-β1, β2 and β3 being found in the CNS. Furthermore, members of several TGF-β subfamilies, e.g., bone morphogenetic proteins (BMPs), growth/differentiation factors (GDFs), activins/inhibins and GDNFs (GDNF, neurturin, artemin, persephin), are widespread in the nervous system. With the exception of GDNF and its relatives, which employ the tyrosine kinase Ret and alpha receptors (GFLalpha1–4) for signaling, they communicate via membrane serine/threonine kinase complexes and use both Smad and non-Smad signaling pathways (Peterziel and Strelau 2006; Heldin et al. 2009; Heldin and Moustakas 2012; Mu et al. 2012). TGF-βs activate numerous immediate early genes that have been implicated in regulating apoptosis and cell cycle, e.g., Klf10 and Klf11 (Spittau and Krieglstein 2012) and TAK1, a TGF-β activated mitogen-activated protein-3 kinase involved in at least five signaling cascades that modulate ischemic brain damage (Ridder and Schwaninger 2012). The signaling network activated by TGF-β is depicted in Fig. 4.

Fig. 4
figure 4

Network of TGF-β-induced genes. Modified from Wendt et al. (2012)

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TGF-βs in neurodegenerative diseases

Since TGF-βs are pleiotropic growth factors with neurotrophic and immunosuppressive properties targeting the entire spectrum of neuronal, glial and inflammatory cells, they unsurprisingly play a leading role in all neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s disease, multiple sclerosis, stroke, neurodepressive disorders and others (Dobolyi et al. 2012). This is best underscored by studying responses to neural lesions in mice lacking distinct TGF-βs (cf. Makwana et al. 2007). In the human Alzheimer brain, levels of TGF-β receptor type II (TβRII) typically expressed on neurons are reduced and correlate with the pathological hallmarks of the disease (Tesseur et al. 2006). Impairment of TGF-β signaling in Alzheimer’s disease implies that the targeting of the neuroprotective TGF-β in this disease might slow down the neurodegenerative processes (Caraci et al. 2012; Wyss-Coray 2006). Midbrain dopaminergic neurons are established target cells for the trophic actions of members of the TGF-β family, most notably the GDNF family ligands (Krieglstein 2006; Roussa et al. 2009; Aron and Klein 2011; Sidorova et al. 2010; Airkasinen and Saarma 2002). Current translational studies are focusing on the development of neurturin for the treatment of Parkinson’s disease (Marks et al. 2010; Bartus et al. 2011, 2012; Bartus 2012). Many studies have revealed the involvement of TGF-βs in the de- and regenerative processes following brain ischemia and stroke (Beck and Schachtrup 2012).

TGF-βs in ocular disease

Among the most stunning effects exerted by TGF-βs is the induction of developmental neuron death in the peripheral nervous system and CNS, including the chick and mouse retina (Krieglstein et al. 2000; Dünker et al. 2001; Dünker and Krieglstein 2003). Immunoneutralization of all three TGF-β isoforms in the chick embryo or deletion of the TGF-β2 and –β3 genes in mice results in the lack of cell death in the peripheral ganglia, spinal cord and retina. Furthermore, neuron death following limb bud ablation in the chick embryo is markedly reduced (Krieglstein et al. 2000). The relevance of these observations in chick and mouse embryos for the biology of adult normal and diseased retinal neurons remains to be explored. As has long been known, detachment of the retina induces the synthesis and secretion or TGF-β2, thereby increasing levels of TGF-β and TβR in Müller cells (Guérin et al. 2001). This might result in the retinal gliotic response and subsequent RGC death. Elevated levels of TGF-β2 are also found in the aqueous humor and reactive optic nerve astrocytes in primary open angle glaucoma (Fuchshofer and Tamm 2012). Available evidence indicates that TGF-β2 contributes to changes in the ECM of the trabecular meshwork and optic nerve head and possibly also to compression of optic nerve axons.

GDNF has been shown to attenuate significantly the degeneration of RGCs in vivo in a dose-dependent fashion (Yan et al. 1999; see also Cui et al. 1999); GDNF also highly effectively rescues photoreceptor function and survival in an animal model of retinal degeneration (Frasson et al. 1999). With regard to underlying mechanisms, photoreceptors interestingly lack the GDNF receptors GFRalpha1 and RET, which, however, are expressed on Müller glial cells. RGCs express the receptors for the GDNF family members neurturin and artemin. The trophic effect of GDNF signaling results from the induction of FGF-2 in Müller glia (Hauck et al. 2006) providing an example for the importance of glia in providing neurotrophic factors. In this context, investigations seem worthwhile into whether the robust survival-promoting effect of GDNF on RGCs can be mediated by a similar indirect mechanism (Yan et al. 1999).

Insulin-like growth factor family

Members of the insulin-like growth factor (IGF) family including IGF-1 and IGF-2 promote cell growth and survival by regulating carbohydrate, lipid and protein metabolism (Bondy et al. 2006). IGF-1 and its receptors are highly expressed in the developing brain and their deletion retards brain growth, diminishes cell size, dendritic arbors and numbers of synapses and causes mental retardation in humans. Exogenously applied IGF-1 can protect injured neurons from cell death. The anabolic effects of IGF-1 are mediated through the PI3K (phosphatidyl inositol 3-kinase)-Akt (also known as protein kinase B) signaling cascade.

The neuroprotective role of IGF-1 has been challenged by the recent analysis of IGF-1-receptor-deficient mice (Torres Aleman 2012). Even so, IGF-1 has been shown to ameliorate hippocampal neurodegeneration in an animal model of temporal lobe epilepsy (Miltiadous et al. 2011) and motor neuron death in type III SMA mice (Tsai et al. 2012). Furthermore, IGF-1 exerts robust protection of cultured neurons against prion peptide-induced death by blocking ROS formation and the translocation of Bax to mitochondria (Y.G. Park et al. 2012). Additional mechanistic studies are required for defining the precise roles of IGF-1 in neurodegenerative diseases.

Several studies have indicated that IGF-1 can protect retinal photoreceptors and axotomized RGCs from death in a variety of lesion paradigms. For example, transcorneal electrical stimulation has been shown to rescue axotomized RGCs by activating the endogenous retinal IGF-1 system (Morimoto et al. 2005). Physiological protection of rod photoreceptors against light stress employs the activation of the IGF-1 receptor and the Akt survival pathway (Dilly and Rajala 2008). In the rd10 mouse model of retinitis pigmentosa, IGF-1 is able to attenuate photoreceptor cell death (Arroba et al. 2011). The pivotal role of IGF-1 in the retina is also underscored by its capacity to induce the increased secretion of vascular endothelial growth factor by the retinal pigment epithelium underlying choroidal neovascularization in age-related macular degeneration (Economous et al. 2008; Cordeiro et al. 2010).

Other growth factor with putative relevance for neuroprotection of RGCs

Additional growth factors and their receptors are expressed in the retina including RGCs but their functions and benefit for neuroprotection have not been systematically studied. For example, RGCs express the hepatocyte growth factor receptor c-Met and the granulocyte macrophage colony stimulating factor alpha receptor; both mediate protection of RGC when activated with their respective ligands (Fischer 2012). In addition, an increasing list of growth factors, e.g., platelet-derived growth factor (Tang et al. 2010) and pituitary adenylate cyclase activiating polypeptide (Atlasz et al. 2010; Seaborn et al. 2011) are being shown to protect against apoptosis in ischemia-induced retinal damage. Beyond the field of growth factors for which receptors have been shown to be expressed in the retina, other factors for which receptors have not been identified are emerging and give stunning neuroprotection in other lesion models. Examples for this category of growth factors that should be mentioned here are the mesencephalic astrocyte-derived neurotrophic factor (MANF; Lindholm et al. 2008) and the conserved dopamine neurotrophic factor (CDNF; Lindholm et al. 2007).

Concluding remarks

In view of the available evidence, cautious optimism is probably the correct attitude to be taken towards the applicability of growth factors for the treatment of neurodegenerative diseases. Among the more than 50 growth factors expressed in the nervous system (Johnson and Tuszynski 2008), only a few have emerged as promising candidates for potential treatments in neurodegenerative diseases. These include BDNF, the TGF-βs GDNF and neurturin and IGF-1. However, significant gaps still have to be filled, from understanding disease pathologies to generating optimal animal models and applicable drugs. Pitfalls along the road to effective growth factor therapies are frequent and even occur on what is considered to be firm ground: a recent example is the observation that GDNF fails to exert neuroprotection in a rat alpha-synuclein model of Parkinson’s disease, a finding that brings into question all previous interpretions of results obtained in preclinical models of this disease (Decressac et al. 2011, 2012a, b). Finally, therapeutic break-throughs can hardly be expected from the administration of a single growth factor or its mimetics: apparently, biology does not work this way. Hence, combinatorial approaches have to be explored more systematically and have to involve survival factors, axon growth promoting molecules and agents to suppress adverse side effects (McCall et al. 2012).