GFP Adeno-associated virus(AAV Serotype 1)

Adeno-associated virus serotype 1-constitutively active Ras homolog enriched in brain [AAV1-Rheb(S16H)] transduction of hippocampal neurons can induce neuron-astrocyte interactions in rat hippocampus in vivo, resulting in neuroprotection. However, whether AAV1-Rheb(S16H) transduction can induce neurotrophic effects and preserve cognitive memory in animal models of Alzheimer's disease (AD) with typical phenotypic features, such as β-amyloid (Aβ) accumulation and cognitive impairment, remains uncertain. Here, researchers show that Rheb(S16H) transduction of hippocampal neurons in 5XFAD mice increases 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. Furthermore, Rheb(S16H) transduction inhibited Aβ production and accumulation in the hippocampus of 5XFAD mice and protected the decline of long-term potentiation (LTP), thereby preventing cognitive impairment, as confirmed by a novel object recognition test. These results suggest that Rheb(S16H) transduction of hippocampal neurons may treat AD by inhibiting Aβ accumulation and preserving LTP associated with cognitive memory.

To examine the effects of Rheb(S16H) transduction on cognitive function in 5XFAD mice, LTP analysis was performed. Theta-burst stimulation (TBS) induced significant synaptic potentiation in hippocampal slices from 6-month-old WT mice (Figure 1A and B); in contrast, TBS-induced LTP in samples from 5XFAD mice were obviously damaged (Figure 1A and B). These results are consistent with previous reports showing significantly reduced LTP levels at hippocampal or cortical excitatory synapses in 5XFAD mice. However, transduction of hippocampal neurons with Rheb(S16H) significantly preserved LTP in 5XFAD mice compared with untreated or AAV1-GFP-treated 5XFAD mice (Figure 1A and B).

Figure 1. Preservation of LTP in the AAV1-Rheb(S16H)-treated 5XFAD mice. (A) Time courses of fEPSP responses before and after TBS from hippocampal slices in WT (black circle), untreated 5XFAD (CON) (red circle), 5XFAD-AAV1-GFP (green circle), and 5XFAD-AAV1-Rheb(S16H) groups (yellow circle). (B) The mean fEPSP amplitude 50–60 min after baseline TBS (mean fEPSP amplitude 10 min before LTP induction). (Moon G J, et al., 2019)