# Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain
## 4 Role of Rheb in Neurodegeneration in the Hippocamp  
As mentioned previously, Rheb augments the expression of NTFs such as BDNF, CNTF, and GDNF through the activation of mTORC1 in the brain. NTFs regulate the development, maintenance, function, and plasticity of mature neurons. BDNF is essential for a basal level of adult hippocampal neurogenesis and the survival and integration of new-born neurons into the hippocampal circuitry [9; 71; 72]. BDNF also plays a crucial role in the early and late phases of LTP, the cellular substrate for learning and memory [9; 71; 72; 73; 74; 75; 76]. Altered BDNF functionality has been observed in different neurodegenerative diseases [77; 78]. Several studies showed that the mRNA and protein expression levels of BDNF and its full-length receptor tropomyosin receptor kinase B (TrkB) are decreased in the hippocampus and neocortex of AD postmortem brains and in the substantia nigra of PD patients [7; 79; 80; 81]. BDNF administration has been shown to improve learning and memory in dement animals [82]. In addition, BDNF has been observed to have neuroprotective effects against \(\beta\)-amyloid (A\(\beta\)) and tau toxicity in AD models [83; 84]. GDNF binds to its co-receptor alpha1 (GFR\(\alpha\)1) and can promote the survival of different neuronal populations in the central and peripheral nervous systems [85]. The Ras/MAPK and PI3K/Akt cascades can be activated when GDNF binds to its main receptor, which consists of the ligand-binding component GFR\(\alpha\) and the tyrosine kinase RET [86; 87]. Several studies on the ability of GDNF to maintain mitochondrial activity have been conducted. By using a mouse model of PD, [PERSON] et al. showed that GDNF could improve impaired mitochondrial function by activating the NF-\(\kappa\)B transcription factor, mediated by the RET kinase through the PI3K pathway [88]. The GDNF-GFR\(\alpha\)1 complex is essential for proper hippocampal circuit development. GDNF-GFR\(\alpha\)1 signaling contributes to synapse development and the maturation of hippocampal neurons [89]. The GDNF-GFR\(\alpha\)1 complex was observed to promote dendritic growth and postsynaptic differentiation in cultured hippocampal neurons through neural cell adhesion (NCAM) signaling [89]. The overexpression of GDNF in hippocampal astrocytes induced the recovery of spatial cognitive abilities in aged impaired rats. Several studies have shown that GDNF can enhance motor functions in aged rats and non-human primates, which may be associated with dopaminergic induction and regeneration of the nigrostriatal pathway [90; 91; 92; 93; 94]. Furthermore, GDNF is known to promote neuronal health and has neural regenerative properties [95]. Low GDNF levels were reported in patients with AD and in 3 xTg AD mice [96; 97]. In addition, GFR\(\alpha\)1 deficiency has been observed in the brain of AD patients [98]. GDNF overexpression in astrocytes was found to exhibit neuroprotective effects through the upregulation of BDNF production, resulting in the preservation of learning and memory in 3 xTg AD mice [99]. In addition, the upregulation of GDNF in activated astrocytes after brain injury is thought to play an active role in neuronal survival and plasticity [100]. Activated astrocytes have been observed to upregulate NTFs, antioxidants, and other key molecules, all of which support neuronal and oligodendrocyte survival as well as tissue repair [101]. These results suggest that the crosstalk between neurons and astrocytes is a potential neuroprotective mechanism of NTFs in neurodegenerative diseases. CNTF belongs to the interleukin-6 family of cytokines and is expressed mainly in astrocytes, whereas CNTF receptor \(\alpha\) subunit (CNTFR\(\alpha\)) is expressed predominantly in neural progenitor cells and hippocampal neurons [102]. CNTF has potent effects on the development and maintenance of the nervous system, inducing neuronal survival and differentiation by stimulating gene expression in sensory, sympathetic, and motor neurons [103].