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

Pérez-González R, Alvira-Botero MX, Robayo O, Antequera D, Garzón M, Martín-Moreno AM, Brera B, de Ceballos ML, Carro E. Gene Ther. (2014) 21(3):298-308.

Speaker: Ji-En Sie (謝季恩)                                 Time: 13:10~14:00, May. 14, 2014

Commentator: Dr. Ai-Li Shiau (蕭璦莉 老師)             Place: Room 601

Abstract:

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. This common form of dementia happens in the elderly and affects many families. One of the AD pathological features is that senile plaques composed by aggregated amyloid-β (Aβ) peptides in the brain cause the neuronal damage and memory loss.¹ In addition, clinical research shows the serum of AD patients contains lower levels of leptin.² In the previous study, leptin receptors exist in brain neurons and leptin exhibits neuroprotective properties including prevention of neuron death and activation of nervous system.³ Thus, the authors used the self-inactive lentivirus vector with leptin gene (HIV-leptin), and stereotaxically injected the vector into brain in APP/PS1 mice model of AD to construct the therapeutic model. First, they observed that memory and recognition ability of the HIV-leptin-treated APP/PS1 mice were restored. Then they confirmed that Aβ plaques accumulation in the cerebral cortex and hippocampus was reduced after treatment with HIV-leptin. The mechanisms of Aβ plaques reduction proved in this study were down-regulation of β-secretase 1 (BACE1) which an enzyme results in Aβ plaques formation and up-regulation of activated microglial which involves in Aβ clearance. On the other hand, the authors found that numbers of neuron synapses were greater and the cell death ratio of synaptosomes was lower in HIV-leptin-treated APP/PS1 mice. Besides, the caspase-3 activity which correlates with synapses deficiency and the procaspase-3 were reduced after treatment with HIV-leptin. Both in vivo and in vitro study showed that synaptophysin, a pre-synaptic marker in synaptosomes, was increased in HIV-leptin-treated APP/PS1 mice. Furthermore, the authors demonstrate that leptin rescued the neuronal length damaged by Aβ. In conclusion, delivery of leptin gene to central nervous system can be a potential gene therapy for AD.

References:

1.     Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. (2001) 81: 741-66.

2.     Power DA et al. Circulating leptin levels and weight loss in Alzheimer’s disease patients. Dement Geriatr Cogn Disord. (2001) 12: 167–170.

3.     Greco SJ et al. Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis. (2010) 19: 1155–1167.