Atorvastatin Protects from Aβ1–40-Induced Cell Damage and Depressive-Like Behavior via ProBDNF Cleavage

Abstract

Intracerebroventricular (icv) amyloid-beta (Aβ) infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aβ infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aβ-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aβ (400 pmol/site, icv) infusion. Aβ-induced hippocampal cell damage was reversed by atorvastatin treatment. Aβ infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aβ-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.

FTO alleviates Aβ1-40 induced retinal pigment epithelium degeneration via PKA/CREB signaling pathway

“…As a functional target of PKA/CREB signaling pathway, mature BDNF(m-BDNF) is derived from pro-BDNF after proteolytic cleavage in the extracellular space [37]. The formation rate of m-BDNF from pro-BDNF was mediated by the expression of pro-BDNF and tPA-and p11-mediated cleavage process [38]. While previous research mainly focused on the neuroprotective factor m-BDNF [39], the pro-apoptosis characteristic of pro-BDNF in AMD are yet fully illuminated.…”

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

“…Another study showed that use of lipophilic statins was associated with more favourable white matter structural integrity in older adults with lower cognitive performance but no dementia diagnosis . Animal models reported beneficial effects of lipophilic (but possibly low BBB‐penetrating) atorvastatin which protected against Aβ‐40 changes in a mouse model, reversed hippocampal cell damage and improved spatial cognition . Statin therapy may also have an effect on dementia biomarkers in the CSF .…”

Simvastatin Therapy Attenuates Memory Deficits that Associate with Brain Monocyte Infiltration in Chronic Hypercholesterolemia

“…Most beneficial effects of simvastatin in the brain are thought to root from the promotion of hippocampal neurogenesis, the inhibition of mesangial cell apoptosis (Qiao, Kang, & Heo, 2011; Robin et al, 2014), the enhancement of neurotrophic factors, and the restriction of inflammation (Esposito et al, 2012). In light of this, simvastatin treatment markedly increased hippocampal expression of BDNF, which has been linked to improved functional recovery after stroke and the amelioration of depressive-like behavior (Ludka et al, 2016; J. Zhang et al, 2017), and may underlie the improvements in hippocampal-dependent memory function we observe in our model.…”