Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice

Abstract

There is growing evidence that leptin is able to ameliorate Alzheimer's disease (AD)-like pathologies, including brain amyloid-β (Aβ) burden. In order to improve the therapeutic potential for AD, we generated a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector (HIV-leptin), and delivered this by intra-cerebroventricular administration to APP/PS1 transgenic model of AD. Three months after intra-cerebroventricular administration of HIV-leptin, brain Aβ accumulation was reduced. By electron microscopy, we found that APP/PS1 mice exhibited deficits in synaptic density, which were partially rescued by HIV-leptin treatment. Synaptic deficits in APP/PS1 mice correlated with an enhancement of caspase-3 expression, and a reduction in synaptophysin levels in synaptosome preparations. Notably, HIV-leptin therapy reverted these dysfunctions. Moreover, leptin modulated neurite outgrowth in primary neuronal cultures, and rescued them from Aβ42-induced toxicity. All the above changes suggest that leptin may affect multiple aspects of the synaptic status, and correlate with behavioral improvements. Our data suggest that leptin gene delivery has a therapeutic potential for Aβ-targeted treatment of mouse model of AD.

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

“…Bath application of leptin reversed LTP suppression induced by acute perfusion of Aβ1-42 in hippocampal slices (Doherty et al, 2013). Leptin gene therapy rescued working memory in an APP/PS1 mouse model of AD in a T-maze task (Perez-Gonzalez et al, 2014). Leptin had beneficial effects on memory consolidation in a water maze task (Oomura et al, 2006) and in leptin-deficient rodents (Li et al, 2002); and leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in the novel object recognition test and fear conditioning test (Farr et al, 2006;Greco et al, 2010).…”

“…PI3-k/Akt is important for protein synthesis (Karpova et al, 2006;Peltier et al, 2007), we suspect that enhancement of synthesis of synaptic proteins may be responsible for reversal of Aβ-induced deficit in L-LTP by leptin treatments. Additionally, leptin also facilitates the uptake of ApoE-bound Aβ and reduces the Aβ level and plaque deposition in an Alzheimer mouse model (TgCRND8) (Fewlass et al, 2004;Greco et al, 2010) and leptin gene therapy prevents the reduction of the number of dendrite spines in the APP/PS1 mouse model (Perez-Gonzalez et al, 2014). Leptin signaling desensitizes in obese patients and some AD patients (Bonda et al, 2014;Lee et al, 2013).…”

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

“…Conversely, the treatment regimen was perfectly suited for PAS-leptin and suggests benefits in clinical settings. It is worth mentioning that not only LD patients should profit from PAS-leptin; several preclinical studies in mice have suggested that individuals suffering from type 1 and type 2 diabetes or neurodegenerative diseases may also benefit from optimised leptin analogues [25][26][27].…”

Leptin: role over central nervous system in epilepsy

“…The latter, highlights the anorexigenic leptin functions that are well described in the literature. However, mounting evidence also suggest other central actions of leptin in multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer, that remain to be better understood [23–25]. …”