Preventive cognitive protection based on AAV9 overexpression of IGF1 in hippocampal astrocytes.

Astrocytes play key roles in the brain. When astrocyte support fails, neurological disorders follow, resulting in disrupted synaptic communication, neuronal degeneration, and cell death. We posit that astrocytes overexpressing neurotrophic factors, such as Insulin Like Growth Factor 1 (IGF1), prevent the onset of neurodegeneration. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a thorough transgene expression along the hippocampus with a single viral injection. Although species typical behavior was impaired, memory deficit was prevented by IGF1. STZ prompted astrocyte shortening, albeit the length of these cells in animals injected with GFP and IGF1 vectors did not statistically differ from the other groups. In STZ control animals, hippocampal microglial reactive cells increased dramatically, but this was alleviated in IGF1 rats. We conclude that overexpression of IGF1 in astrocytes prevents neurodegeneration onset. Hence, individuals with early neurotrophic exhaustion would be vulnerable to age-related neurodegeneration.

The specific inhibition of the cardiac electrogenic sodium/bicarbonate cotransporter leads to cardiac hypertrophy.

Two alkalinizing mechanisms coexist in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has previously been reported to be responsible for the development of cardiovascular diseases. The aim of this study was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1 expression, we cloned shRNA into a cardiotropic adeno-associated vector (AAV9-shNBCe1). After 28 days of being injected with AAV9-shNBCe1, the expression and the activity of NBCe1 in the rat heart were reduced. Strikingly, downregulation of NBCe1 causes significant hypertrophic heart growth, lengthening of the action potential in isolated myocytes, an increase in the duration of the QT interval and an increase in the frequency of Ca2+ waves without any significant changes in Ca2+ transients. An increased compensatory expression of NBCn1 and NHE1 was also observed. We conclude that reduction of NBCe1 is sufficient to induce cardiac hypertrophy and modify the electrical features of the rat heart.