Therapeutic Potential of AAV1-Rheb(S16H) Transduction Against Alzheimer’s Disease

Abstract

We recently reported that adeno-associated virus serotype 1-constitutively active Ras homolog enriched in brain [AAV1-Rheb(S16H)] transduction of hippocampal neurons could induce neuron-astroglia interactions in the rat hippocampus in vivo, resulting in neuroprotection. However, it remains uncertain whether AAV1-Rheb(S16H) transduction induces neurotrophic effects and preserves the cognitive memory in an animal model of Alzheimer’s disease (AD) with characteristic phenotypic features, such as β-amyloid (Aβ) accumulation and cognitive impairments. To assess the therapeutic potential of Rheb(S16H) in AD, we have examined the beneficial effects of AAV1-Rheb(S16H) administration in the 5XFAD mouse model. Rheb(S16H) transduction of hippocampal neurons in the 5XFAD mice increased the levels of neurotrophic signaling molecules, including brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), and their corresponding receptors, tropomyosin receptor kinase B (TrkB) and CNTF receptor α subunit (CNTFRα), respectively. In addition, Rheb(S16H) transduction inhibited Aβ production and accumulation in the hippocampus of 5XFAD mice and protected the decline of long-term potentiation (LTP), resulting in the prevention of cognitive impairments, which was demonstrated using novel object recognition testing. These results indicate that Rheb(S16H) transduction of hippocampal neurons may have therapeutic potential in AD by inhibiting Aβ accumulation and preserving LTP associated with cognitive memory.

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

“…The activation of mTORC1 induced by Rheb(S16H) transduction of hippocampal neurons was found to result in BDNF production, which protected against thrombin-induced neurotoxicity in the rat hippocampus [5]. In the same manner, AAV1-Rheb(S16H) transduction in the hippocampus of transgenic AD mice prevented cognitive function impairment [26,29].…”

“…The mutation of serine to histidine at position 16 of Rheb [Rheb(S16H)] has been found to exhibit gain-of-function properties, resulting in highly activated mTOR signaling in TSC1/2-overexpressing cells [128]. Our previous studies showed that the overexpression of Rheb(S16H) could significantly increase the levels of NTFs such as GDNF, CNTF, and BDNF in the adult brain [5,11,26,29,69]. The mutation of tyrosine to asparagine at position 35 of Rheb [Rheb(Y35N)] in renal cell carcinoma has been reported to cause mTORC1 hyperactivation by increasing the resistance to TSC2 GAP activity, resulting in the hyperproliferation of tumor cells [129].…”

“…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 5XFAD 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.…”

“…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].…”

“…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].…”