# Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain
## 1 Introduction  
Neurodegenerative diseases, which are becoming increasingly prevalent, are characterized by the physical decay and eventual loss of neurons. Neurodegenerative changes within the hippocampus and an extended neuronal network involving the medial temporal and medial parietal lobes result in the memory impairment observed in Alzheimer's disease (AD) [1, 2]. AD is the result of slow neuron degeneration, which starts in the hippocampus and spreads to the rest of the brain. The hippocampus plays a strategic role in the neurobiology of memory, being involved in the hierarchical spread of amyloid and neurofibrillary tangles [3, 4]. The World Health Organization has identified dementia caused by AD as a public health priority, which will affect an estimated 115 million people worldwide by 2050 if there is no effective preventative strategy. Despite progress in elucidating the underlying mechanisms and genes involved in certain hallmarks of AD, including neuronal degeneration, extracellular neuritic plaques, and intracellular neurofibrillary tangles, the mechanisms underlying the degeneration and functional disruption that occur in AD remain unknown, and treatments to prevent the progression of the disease are limited [1, 5, 6]. Although the incomplete understanding of the etiology of AD hinders the development of knowledge-based targeted therapeutics, various studies have demonstrated that alterations in the levels of specific neurotrophic factors (NTFs), suchas brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), are associated with the pathogenesis of neurodegenerative diseases such as AD and Parkinson's disease (PD) [5; 7; 8; 9; 10; 11; 12; 13]. These observations suggest that the sustained expression of neurotrophic factors may be useful for protecting neurons in the adult brain, and the regulatory system of a key molecule that can produce neurotrophic factors is a potential therapeutic target against neurodegenerative diseases.  
Ras homolog protein enriched in brain (Rheb) is a member of the Ras superfamily containing Rheb1 and Rheb2 [14]. Rheb is expressed at high basal levels in the hippocampus, cerebral cortex, occipital pole, frontal lobe, and temporal lobe [15]. Rheb is biochemically activated by growth factors such as epithelial growth factor (EGF), fibroblast growth factor (FGF), glial cell line-derived neurotrophic factor (GDNF), CNTF, and BDNF and it is associated with neuronal growth, differentiation, aging, axonal regeneration, energy homeostasis, autophagy, and amino acid uptake [16; 17]. It is well known that Rheb functions as a key activator of mammalian target of rapamycin complex 1 (mTORC1), and the deletion of Rheb could lead to reduced cortical thickness and defective myelination in the brain [18]. Rheb could negatively regulate autophagy [19], resulting in protein aggregation, which can be associated with the progression and severity of neurodegenerative diseases such as AD, PD, and Huntington disease (HD) [20; 21; 22; 23]. However, there has been accumulating evidence of the neuroprotective effects of enhanced Rheb expression against neurodegenerative diseases including PD [11; 24; 25], AD [26; 27], and spinal cord injury [28]. Interestingly, the hyperactivation of Rheb could protect hippocampal neurons via neurotrophic interactions between neurons and astrocytes against neurotoxic conditions in the hippocampus of the adult brain [5; 26; 29; 30].  
A cure for neurodegenerative diseases has not been developed; however, accumulating evidence suggests that Rheb may be considered as one of the possible treatment targets for neurodegenerative diseases due to its pleiotropic role in the production of various NTFs. Therefore, this study provides insight into the role of Rheb signaling pathways in neurodegenerative diseases and the beneficial effects of Rheb as a potential therapeutic agent against hippocampal neurodegeneration in the adult brain.