Neuroprotective Effects Of A Low Molecular Weight Peptide As Mimetic Of BDNF In Alzheimer’s Disease Models

Back ground:Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with specific pathological changes resulting in progressive development of dementia. Since the life expectancy is increasing in most countries, the incidence of AD presents an ascending trend which has brought a heavy burden to family and society. Due to the complexity of its etiology and pathogenesis, no disease-modifying treatment is available today. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has survival and growth-promoting actions on a variety of neurons, including dorsal root ganglion cells, hippocampal and cortical neurons, and certain peripheral sensory neurons. BDNF is thought to exert its biological activity by binding to the membrane traversing tyrosine kinase TrkB receptor and activating several signal transduction pathways. Despite lots of promising pre-clinical data, there are many properties limiting the therapeutic application of BDNF, for instance, the short plasma half-life (less than1min in rats) and poor blood-brain barrier penetration. Therefore, we developed a novel fusion peptide composed of BDNF mimetic peptide and the transduction domain of human immunodeficiency virus (HIV) TAT that can cross the blood-brain barrier (BBB).Aim:To investigate whether this novel fusion peptides has neuroprotective effects in Alzheimer’s disease models and explore the potential mechanism.Methods:We first evaluated the ability of the fusion peptide to cross the blood-brain barrier with EGFP-TAT, and then examined its effects on scopolamine-induced amnesia rats and APP transgenic mice. The Morris water maze was used to test the animals’ learning and memory. The expression levels of TrkB receptor and downstream signaling molecules, as well as the synapse-associated proteins were measured by western blotting and immunohistochemistry. Activities of AChE and ChAT were detected by enzyme activity assay kits.Results:We found (1) that TAT has the ability of delivering protein to cross the blood-brain barrier into the rodent central nervous system (CNS).(2) That the fusion peptide ameliorates scopolamine-induced learning and memory impairments in rats with increases of synaptophysin and M receptor and decrease of the acetylcholinesterase (AChE) activity.(3) That the fusion peptide attenuates spatial learning and memory deficits in APP transgenic mice with decreases of Aβ and tau hyperphosphorylation and elevation of several synapse-associated proteins. The potential mechanism involves activation of TrkB receptor and the downstream signaling molecules Erkl/2and Akt, as well as the improved expressions of transcription factor CREB and immediate early gene Arc.Conclusions:The novel fusion peptide penetrates the blood-brain barrier and attenuates spatial learning and memory deficits in Alzheimer’s disease models through activation of TrkB receptor and downstream signaling molecules.