# Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain
## 4 Role of Rheb in Neurodegeneration in the Hippocamp
In addition, the neuroprotective properties of CNTFdemonstrate that it is a survival factor for sympathetic, sensory, and hippocampal neurons. CNTF could promote neural stem cell division directly through its receptor [104]. It has been reported that CNTF protects neurons from degeneration arising from multiple etiologies [105; 106]. In a previous study, CNTF contributed to the full recovery of cognitive functions associated with the stabilization of synaptic protein levels in the Tg2576 AD mouse model [107]. These results indicate the potential of CNTF as a therapeutic agent for treating neurodegenerative diseases. Taken together, increasing evidence suggests that a lack of trophic support may contribute significantly to neurodegeneration, and NTFs have emerged as promising therapeutic agents for neurodegenerative diseases [108]. Nevertheless, the clinical utility of systemic BDNF, GDNF, and CNTF is limited by poor blood-brain barrier (BBB) permeability, a short half-life, and off-target effects [109; 110]. Rheb has been reported to increase the levels of acetylcholine and total choline in the adult rat brain, which are important for maintaining cognitive functions in AD brains [5]. Axon degeneration and synapse and dendritic spine loss have been observed in brains as a result of aging and neurodegenerative diseases [111; 112; 113]. A decrease in synaptic connectivity is considered to be a major cause of altered mood and impaired perception and cognition in neurodegenerative diseases. Several studies have demonstrated the role of Rheb-mTOR signaling in axon elongation and synaptic morphogenesis [114; 115]. Akt-Rheb-mTOR signaling can enhance not only the axon length but also the axon number per neuron and the number of neurons having multiple axons [116]. In addition, Rheb activation can enhance dendritic morphogenesis and synaptic integration in the subventricular zone [117]. TSC2-Rheb-mTOR signaling regulates the ephrin-Eph receptor system to mediate axon guidance in the visual system [118]. Furthermore, long-term synaptic plasticity, learning, and memory rely on de novo protein synthesis. Rheb-mTOR signaling is considered an important mechanism for the maintenance of LTP and learning and memory functions [60; 61]. Rheb has been reported to interact with beta-secretase 1 (BACE1) in the mouse brain, resulting in the inhibition of BACE1 activity and the reduction of A\(\beta\) generation [119]. Furthermore, the deletion of Rheb could lead to deficits in spatial memory functions, a behavioral hallmark of AD progression [119]. In the brain of patients with AD, the levels of Rheb are significantly downregulated compared with its levels in a normal healthy brain [23]. On the other hand, Rheb can be an issue in neurodegenerative disease progression. Several studies indicated that TSC-Rheb-mTOR signaling could regulate aggresome formation, contributing to the disposal of misfolded proteins via the proteasome and autophagy system. Autophagy failure can trigger neuronal cell death in several ways, depending on where the defect is along the pathway. When proteolytic clearance steps are compromised, autolysosomes/lysosomes accumulate mutant and oxidized proteins, protein oligomers and aggregates, damaged organelles, and other incompletely digested products, some of which increase the permeability of lysosomal membranes and cause hydrolases to be released into the cytoplasm, in some cases even from otherwise intact lysosomes [112]. Autophagy-related pathology has been noted in late-onset neurodegenerative diseases including AD, PD, amyotrophic lateral sclerosis (ALS), and HD [23]. mTORC1 negatively controls the initiation of autophagy, contributing to the formation of pathological protein aggregates. Previous studies [120; 121] showed that mTOR activation could downregulate A\(\beta\) clearance by inhibiting autophagy functions with the suppression of several signaling pathways including PI3K/Akt, glycogen synthase kinase 3 (GSK-3), AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1) [122].