# Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain
## 6 Mechanisms of Rheb(S16H)-Induced Neuroprotection in the Hippocamp of the Adult Brain  
To date, the upregulation of neuronal Rheb(S16H) has demonstrated some beneficial effects in the hippocampus of the adult brain under neurotoxic conditions. Our previous studies demonstrated that neuronal transduction with AAV1-Rheb(S16H) prevented thrombin-induced neuronal death in the hippocampus of the adult rat brain [5; 29]. Similarly, previous studies reported that neuronal transduction of Rheb(S16H) could protect dopaminergic neurons in the substantia nigra of mice against neurotoxin-induced dopamine neuronal death [11; 24; 25; 69] and prothrombin kringle-2 (pKr-2)-induced neurotoxic inflammation [30]. AAV1-Rheb(S16H) transduction was found to have preventive effects on LTP impairment and cognitive decline in 5 XFAD mice, which represent a transgenic mouse model of AD carrying five mutations associated with early-onset familial Alzheimer's disease (FAD) [26]. These neuroprotective effects could be mediated by the stimulation of mTORC1-related neuronal BDNF production following AAV1-Rheb(S16H) administration, which might occur regardless of the levels of neuroinflammatory molecules. In addition, we recently found that neuronal transduction with AAV1-Rheb(S16H) could increase the expression of GDNF in both hippocampal neurons and astrocytes via autocrine and paracrine BDNF-TrkB signaling [29; 135]. Similarly, previous studies reported that the expression of neuronal Rheb(S16H) could protect dopaminergic neurons through the elevation of GDNF and BDNF expression in the substantia nigra against neurotoxin-induced dopamine neuronal death [69] and pKr-2-induced neurotoxic inflammation [30]. Furthermore, Rheb(S16H) upregulation could induce the upregulation of cAMP response element-binding protein (CREB) phosphorylation in dopamine neurons, which may be associated with the synthesis of GDNF and BDNF. In the hippocampus of the adult brain, AAV1-Rheb(S16H) transduction could induce sustained increases in the levels of full-length TrkB and CNTFR\(\alpha\) in reactive astrocytes and hippocampal neurons, respectively [29]. In addition, we demonstrated that neuronal BDNF produced by the transduction of hippocampal neurons with Rheb(S16H) could induce reactive astrocytes, which could lead to CNTF production through the activation of astrocytic TrkB and the upregulation of neuronal BDNF and astrocytic CNTF, resulting in synergistic effects on the survival of hippocampal neurons in vivo [29]. In 5 XFAD mice, AAV1-Rheb(S16H) transduction was found to have preventive effects on LTP impairment and cognitive decline [26]. These beneficial effects may be attributed to the interaction between neurons and astrocytes promoted by multiple NTFs induced by Rheb(S16H) transduction of hippocampal neurons, which result in neuroprotection in the hippocampus of 5 XFAD mice. Astrocytes are the most abundant cells in the brain and play an important role in the homeostatic maintenance of physiological environments, such as ion concentration and pH in the central nervous system [136; 137]. Although previous studies indicated that astrocyte activation is involved in neurodegeneration through inflammatory responses in the adult brain [138; 139], reactive astrocytes may have beneficial effects such as increased neuronal survival, growth, and activity through barrier function to restrict tissue damage and neuroinflammatory [137; 140; 141]. In addition, they have been found to produce NTFs such as GDNF and CNTF in animal models of neurodegenerative diseases [142; 143; 144]. A study reported that the loss of astrocytes in the brain of GFAP-knockout mice resulted in a larger infarct area induced by ischemic brain injury following middle cerebral artery occlusion [145]. Overall, these findings suggest that astrocytes are important for maintaining a normal neural system in the adult brain.